Methods of treating crohn&#39;s disease and ulcerative colitis

ABSTRACT

The present disclosure is directed to methods for treating Crohn&#39;s disease, and in particular, to methods for inducing clinical remission and/or endoscopic improvement of Crohn&#39;s disease, using a JAK1 inhibitor. In certain embodiments, the patient is administered an induction dose of the JAK1 inhibitor to induce clinical remission and/or endoscopic improvement of the Crohn&#39;s disease, followed by administration of at least one maintenance dose of the JAK1 inhibitor thereafter. In other embodiments, the present disclosure is directed to methods for treating ulcerative colitis using a JAK1 inhibitor.

RELATED APPLICATIONS

This application is a continuation in part of U.S. patent applicationSer. No. 17/667,748, filed Feb. 9, 2022, which claims priority to U.S.Provisional Application No. 63/151,429, filed Feb. 19, 2021, U.S.Provisional Application No. 63/211,412, filed Jun. 16, 2021, and U.S.Provisional Application No. 63/285,916, filed Dec. 3, 2021, and is acontinuation in part of U.S. patent application Ser. No. 17/115,833,filed Dec. 9, 2020, which is a continuation of U.S. patent applicationSer. No. 15/917,013, filed Mar. 9, 2018, which claims priority to U.S.Provisional Application No. 62/469,337, filed Mar. 9, 2017, U.S.Provisional Application No. 62/470,565, filed Mar. 13, 2017, U.S.Provisional Application 62/483,289, filed Apr. 7, 2017 and U.S.Provisional Application No. 62/593,629, filed Dec. 1, 2017, each ofwhich is incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

The present disclosure is directed to methods for treating inflammatorybowel diseases, such as Crohn's disease and ulcerative colitis, and inparticular, to methods for inducing clinical remission and endoscopicimprovement of Crohn's disease or a clinical remission and endoscopicimprovement of ulcerative colitis, using a JAK1 inhibitor. In certainembodiments, the patient is administered an induction dose of the JAK1inhibitor to induce clinical remission and/or endoscopic improvement ofthe Crohn's disease or a clinical remission of ulcerative colitis,followed by administration of at least one maintenance dose of the JAK1inhibitor thereafter.

BACKGROUND OF THE DISCLOSURE

Inflammatory bowel disease (IBD) involves chronic inflammation of apatient's digestive tract. IBD includes both Crohn's disease andulcerative colitis. The exact cause of IBD is not known. The IBD can beidiopathic IBD.

Crohn's Disease (CD) encompasses a spectrum of clinical and pathologicalprocesses manifested by focal asymmetric, transmural, and occasionallygranulomatous inflammation that can affect any segment of thegastrointestinal tract (Lichtenstein G R, Hanauer S B, Sandborn W J;Practice Parameters Committee of American College of Gastroenterology,Management of Crohn's disease in adults, Am J Gastroenterol. 2009;104(2):465-83). The disease can affect persons of any age, and its onsetis most common in the second and third decades. Females are affectedslightly more than males, and the risk for disease is higher in someethnic groups (Loftus E V Jr., “Clinical epidemiology of inflammatorybowel disease: incidence, prevalence, and environmental influences,”Gastroenterology, 2004; 126(6):1504-17; Probert C S, Jayanthi V, RamptonD S, et al., “Epidemiology of inflammatory bowel disease in differentethnic and religious groups: limitations and aetiological clues,” Int. JColorectal Dis., 1996; 11(1):25-28). In North America, the incidence ofCD is estimated to be 3.1 to 14.6 cases per 100,000 persons. Prevalencerates range from 26 to 99 cases per 100,000 persons. In Europe, CD hasan incidence of 0.7 to 9.8 cases per 100,000 persons and a prevalence of8.3 to 214 cases per 100,000 persons (Loftus E V Jr. Clinicalepidemiology of inflammatory bowel disease: incidence, prevalence, andenvironmental influences. Gastroenterology. 2004; 126(6):1504-17).

CD has been characterized by significant morbidity including abdominalpain, diarrhea, weight loss/malnutrition, fatigue and a progressivenature that leads to complications such as fistulas, strictures andabscesses. In a population based study from southeastern Norway, asubstantial number of patients demonstrated a stricturing or penetratingphenotype at 10 years after diagnosis (Solberg I C, Vatn M H, Hoie O, etal; IBSEN Study Group. Clinical course in Crohn's disease: results of aNorwegian population-based ten-year follow-up study. Clin GastroenterolHeptaol. 2007; 5(12):1430-8). Moreover, approximately 80% of patientsdiagnosed with CD will require at least 1 surgery related to the diseaseat some point in time (Munkholm P, Langholz E, Davidsen M, et al.Intestinal cancer risk and mortality in patients with Crohn's disease.Gastroenterology. 1993:105(6):1716-23).

Ulcerative colitis (UC) is one of the two primary forms of idiopathicinflammatory bowel disease (IBD). It is postulated that UC is caused byunregulated and exaggerated local immune response to environmentaltriggers in genetically susceptible individuals (Hanauer S B. Update onthe etiology, pathogenesis and diagnosis of ulcerative colitis. Nat ClinPract Gastroenterol Hepatol. 2004; 1(1):26-31). UC is a chronic,relapsing inflammatory disease of the large intestine characterized byinflammation and ulceration of mainly the mucosal and occasionallysubmucosal intestinal layers. The highest annual incidence of UC was24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years inAsia and the Middle East, and 19.2 per 100,000 person-years in NorthAmerica, with a prevalence of 505 cases per 100,000 persons in Europeand 249 cases per 100,000 persons in North America. (Molodecky N A, SoonI S, Rabi D M, et al. Increasing incidence and prevalence of theinflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012:142(1):46-54). There is increasing incidence andprevalence of the inflammatory bowel diseases with time, based onsystematic review. (Gastroenterology. 2012; 142(1):46-54.e42; quiz e30.)The burden of UC on the healthcare system is profound, accounting fornearly 500,000 physician visits and more than 46,000 hospitalizationsper year in the United States (US) alone. (Sandler R S, Everhart J E,Donowitz M, et al., Gastroenterology, 2002; 122(5):1500-11).

The hallmark clinical symptoms of UC include bloody diarrhea associatedwith rectal urgency and tenesmus. The clinical course is marked byexacerbation and remission. The diagnosis of UC is suspected on clinicalgrounds and supported by diagnostic testing, and elimination ofinfectious causes. (Dignass A, Eliakim R, Magro F, et al. SecondEuropean evidence-based consensus on the diagnosis and management ofulcerative colitis part 1: definitions and diagnosis. J Crohn's Colitis.2012; 6(10):965-90)

The most severe intestinal manifestations of UC are toxic megacolon andperforation. Extraintestinal complications include arthritis (peripheralor axial involvement), dermatological conditions (erythema nodosum,aphthous stomatitis, and pyoderma gangrenosum), inflammation of the eye(uveitis), and liver dysfunction (primary sclerosing cholangitis).Patients with UC are at an increased risk for colon cancer, and the riskincreases with the duration of disease as well as extent of colonaffected by the disease. (Rutter M, Saunders B, Wilkinson K, et al.Severity of inflammation is a risk factor for colorectal neoplasia inulcerative colitis. (Gastroenterology, 2004; 126(2):451-9).

The aim of medical treatment in UC is to control inflammation and reducesymptoms. Available pharmaceutical therapies are limited, do not alwayscompletely abate the inflammatory process, and may have significantadverse effects. Therapies for mild to moderate active UC include5-aminosalicylic acid derivatives and immunosuppressants.

Corticosteroids are used in patients with more severe UC symptoms butare not useful for longer term therapy. (Truelove S C, Witts L J.Cortisone and corticotrophin in ulcerative colitis. Br Med 1959;1(5119):387-94). The frequency and severity of corticosteroid toxicitiesare significant, including infections, emotional and psychiatricdisturbances, skin injury, and metabolic bone disease. Corticosteroidsare not effective for the maintenance of remission and the UC practiceguidelines from the American College of Gastroenterology recommendagainst chronic steroid treatment. (Kornbluth A, Sachar D B; PracticeParameters Committee of the American College of Gastroenterology.Ulcerative colitis practice guidelines in adults: American College ofGastroenterology, Practice Parameters Committee. Am J Gastroenterol.2010; 105(3):501-23; quiz 524). Patients with moderate to severesymptoms may derive some benefits from immunosuppressant agents(azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]);however, the use of these agents is limited as induction treatment dueto a slow onset of action (3 to 6 months) and as maintenance therapy dueto adverse events (AEs), including bone marrow suppression, infections,hepatotoxicity, pancreatitis, and malignancies. (Kornbluth A, Sachar DB; Practice Parameters Committee of the American College ofGastroenterology. Ulcerative colitis practice guidelines in adults:American College of Gastroenterology, Practice Parameters Committee. AmJ Gastroenterol., 2010; 105(3):501-23; quiz 524; Beaugerie L, Brousse N,Bouvier A M, et al. Lymphoproliferative disorders in patients receivingthiopurines for inflammatory bowel disease: a prospective observationalcohort study. Lancet. 2009; 374(9701):1617-25). Despite these therapies,approximately 15% of ulcerative colitis patients experience a severeclinical course, and 30% of these patients require removal of thecolon/rectum, to eliminate the source of the inflammatory process,although accompanied by significant morbidity (Aratari A, Papi C,Clemente V, et al. Colectomy rate in acute severe ulcerative colitis inthe infliximab era. Dig Liver Dis. 2008; 40(10):821-6; Turner D, Walsh CM, Steinhart A H, et al. Response to corticosteroids in severeulcerative colitis: a systematic review of the literature and ameta-regression. Clin Gastroenterol Hepatol. 2007; 5(1):103-10).

Biological agents targeting specific immunological pathways have beenevaluated for their therapeutic effect in treating patients with UC.Anti-tumor necrosis factor (TNF) agents were the first biologics to beused for IBD. Infliximab, adalimumab, and golimumab are successfullybeing used for the treatment of UC. Recently, vedolizumab, ananti-adhesion therapy, has been approved for the treatment of UC by theUS Food and Drug Administration (FDA) and the European Medicines Agency(EMA), and clinical development is ongoing in Japan.

Anti-TNF therapies are an effective treatment for patients who aresteroid refractory or steroid dependent, who had inadequate response toa thiopurine, or who are intolerant to these medications. Potentialrisks with anti-TNF therapies include infusion or injection sitereactions, serious infections, lymphoma, heart failure, lupus-likesyndromes, and demyelinating conditions (Sandborn W J. State-of-the-art:immunosuppression and biologic therapy. Dig Dis. 2010; 28(3):536-42).Despite the beneficial results achieved with the available biologicagents, only 17% to 45% of patients who receive them are able to achieveclinical remission. (Rutgeerts P, Sandborn W, Feagan B, et al.,Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005, 353(23):2462-76; Sandborn W J, van Assche G,Reinisch W, et al. Adalimumab induces and maintains clinical remissionin patients with moderate-to-severe ulcerative colitis.Gastroenterology, 2012, 142(2):257-65; Feagan B, Greenberg G, Wild G, etal., Treatment of ulcerative colitis with a humanized antibody to thealpha4beta7 integrin, N. Engl. J. Med. 2005, 352(24):2499-507; SandbornW, Feagan B, Marano C, et al. Subcutaneous golimumab induces clinicalresponse and remission in patients with moderate-to-severe ulcerativecolitis, Gastroenterology, 2014, 146(1): 85-95; quiz e14-5), Thus, thereremains a clear medical need for additional therapeutic options in UCfor patients with inadequate response to or intolerance to conventionaltherapies and biologic therapies

Given that no known medical or surgical cure currently exists for CD,the therapeutic strategy is to reduce symptoms, improve quality of life,reduce endoscopic evidence of inflammation, and minimize short- and longterm toxicity and complications (Lichtenstein G R, Hanauer S B, SandbornW J; Practice Parameters Committee of American College ofGastroenterology, Management of Crohn's disease in adults, Am JGastroenterol., 2009, 104(2):465-83). Currently, patients with moderateto severe disease are usually treated with conventional pharmacologicinterventions, which include corticosteroids and immunosuppressantagents such as azathioprine, 6-mercaptopurine, or methotrexate (MTX)(Lichtenstein G R, Hanauer S B, Sandborn W J, Practice ParametersCommittee of American College of Gastroenterology, Management of Crohn'sdisease in adults, Am J Gastroenterol, 2009, 104(2):465-83; Dignass A,Van Assche G, Lindsay J O, et al., European Crohn's and ColitisOganisation (ECCO), The second European evidence-based Consensus on thediagnosis and management of Crohn's disease: current management, JCrohn's Colitis, 2010, 4(1):28-62, Erratum in: J Crohn's Colitis, 2010,4(3):353).

The potential risks from long term use of corticosteroids arewell-known. Adverse events (AEs) associated with short-term use ofcorticosteroids include acne, moon face, edema, skin striae, glucoseintolerance, and sleep/mood disturbances, while potential AEs observedwith longer term use (usually 12 weeks or longer but sometimes shorterdurations) include posterior subcapsular cataracts, osteoporosis,osteonecrosis of the femoral head, myopathy, and susceptibility toinfection (Irving P M, Gearry R B, Sparrow M P, et al., Review article:appropriate use of corticosteroids in Crohn's disease, Aliment PharmacolTher., 2007, 26(3):313-29; Rutgeerts P J, Review article: thelimitations of corticosteroid therapy in Crohn's disease, AlimentPharmacol Ther., 2001, 15(10):1515-25). The safety risks forazathioprine and 6-mercaptopurine include pancreatitis, bone marrowdepression, infectious complications, and malignant neoplasms (Sandborn,W J, State-of-the-art: immunosuppression and biologic therapy, Dig Dis.,2010, 28(3):536-42). MTX may be associated with nausea, bone marrowdepression and liver and pulmonary toxicity (Siegel, et al., Reviewarticle: Practical Management of Inflammatory Bowel Disease PatientsTaking Immunosuppressants, Aliment Pharmacol Ther., 2005, 22:1-16).Patients who do not respond to conventional therapies are treated withanti-TNF-α therapies (i.e., biologics) (Lichtenstein G R, Hanauer S B,Sandborn W J, Practice Parameters Committee of American College ofGastroenterology, Management of Crohn's disease in adults, Am JGastroenterol., 2009, 104(2):465-83; Dignass A, Van Assche G, Lindsay JO, et al., European Crohn's and Colitis Oganisation (ECCO), The secondEuropean evidence-based Consensus on the diagnosis and management ofCrohn's disease: current management, J Crohn's Colitis, 2010,4(1):28-62, Erratum in: J Crohn's Colitis, 2010, 4(3):353). Potentialrisks with biologics include infusion or injection site reactions,serious infections, lymphoma and other malignancies, heart failure,cytopenias, lupus-like syndromes, and demyelinating conditions (SandbornW J, State-of-the-art: immunosuppression and biologic therapy, Dig.Dis., 2010, 28(3):536-42).

Despite the beneficial results achieved with the available anti-TNF-αagents, approximately 40% of patients who receive them for the firsttime do not have a clinically meaningful response (primarynonresponders) (Targan S R, Hanauer S B, van Deventer S J, et al., Ashort-term study of chimeric monoclonal antibody cA2 to tumor necrosisfactor alpha for Crohn's disease, N Engl. J. Med., 1997,337(15):1029-35; Hanauer S B, Feagan B G, Lichtenstein G R, et al.,ACCENT I Study Group, Maintenance infliximab for Crohn's disease: theACCENT I randomized trial, Lancet, 2002, 359(9317):1541-9; Hanauer S B,Sandborn W J, Rutgeerts P, et al., Human anti-tumor necrosis factormonoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-Itrial, Gastroenterology, 2007, 132(1):52-65; Colombel J F, Sandborn W J,Rutgeerts P, et al., Adalimumab for maintenance of clinical response andremission in patients with Crohn's disease: the CHARM trial,Gastroenterology, 2007, 132(1):52-65; Sandborn W J, Feagan B G, StoinovS, et al., PRECISE I Study Investigators, Certolizumab pegol for thetreatment of Crohn's disease, N Engl. J Med., 2007, 357(3):228-38).Among patients who initially respond and continue to receive maintenancetreatment for longer durations, approximately 38% become nonrespondersafter 6 months (Schribeinger S, Khaliq-Kareemi M, Lawrance I C, et al;PRECISE 2 Study Investigators, Maintenance therapy with certolizumabpegol for Crohn's disease, N Engl. J Med., 2007, 357(3):239-50, Erratumin: N Engl. J Med., 2007, 357(13):1357) and approximately 50% becomenonresponders at 1 year lose response (secondary nonresponders) (HanauerS B, Feagan B G, Lichtenstein G R, et al., ACCENT I Study Group,Maintenance infliximab for Crohn's disease: the ACCENT I randomizedtrial, Lancet, 2002, 359(9317):1541-9; Colombel J F, Sandborn W J,Rutgeerts P, et al., Adalimumab for maintenance of clinical response andremission in patients with Crohn's disease: the CHARM trial,Gastroenterology, 2007, 132(1):52-65). Patients who initially respond toa first anti-TNF agent but then lose response tend to have lowerresponse and remission rates to the second anti-TNF agent (Colombel J F,Sandborn W J, Rutgeerts P, et al., Adalimumab for maintenance ofclinical response and remission in patients with Crohn's disease: theCHARM trial, Gastroenterology, 2007, 132(1):52-65; Sandborn, et al.,“Natalizumab induction and maintenance therapy for Crohn's disease,” NEngl. J. Med., 2005, 353(18):1912-25).

New classes of biologics have been studied in patients with prioranti-TNF use. Natalizumab, a humanized monoclonal antibody to α4β1 andα4β7 integrins, showed promise for patients with prior exposure toanti-TNF-α therapy; more than half of the patients had a response to theinduction regimen (Sandborn, et al., “Natalizumab induction andmaintenance therapy for Crohn's disease,” N. Engl. J. Med., 2005,353(18):1912-25). However, natalizumab's use after approval in 2008 hasbeen severely limited due to the serious risk for progressive multifocalleukoencephalopathy (PML) attributed to activation of the latent JCvirus (Van Assche G, Van Ranst M, Sciot R, et al., “Progressivemultifocal leukoencephalopathy after natalizumab therapy for Crohn'sdisease,” N. Engl. J. Med., 2005, 353(4):362-8). Vedolizumab is specificto the α4β7 integrin, which does not affect lymphocyte trafficking tothe brain. Therefore, it is presumed to not have the PML risk associatedwith natalizumab. However, it does not fulfill many of the unmet needsof patients who have failed treatment with anti-TNFs, such as theimprovement of extra-intestinal manifestations (Rubin, et al.,Inflammatory Bowel Diseases, 2016, 22 Suppl. 1: S42-S43). In theinduction study with vedolizumab, the primary endpoint of clinicalremission in patients who had previously failed treatment with an antiTNF was not statistically significant nor was it clinically meaningfulsince there was only a 3% difference from placebo (Sands, et al.,“Effects of Vedolizumab Induction Therapy for Patients with Crohn'sDisease in Whom Tumor Necrosis Factor Antagonist Treatment Failed,”Gastroenterology, 2014, 147:618-627). Ustekinumab, a human monoclonalantibody that selectively targets IL-12 and IL-23, has efficacy in bothpatients who have responded to and patients who have not responded toprior anti-TNFα therapy. The efficacy of ustekinumab, however, isbroadly similar to that of anti-TNF agents, and therefore subject tosimilar drawbacks (Ther. Adv. Gastroenterology, 2016, Vol. 9(1), pp.26-36). Clearly, the need for additional therapeutic options in CD forpatients who fail or are intolerant to conventional therapies, andanti-TNF-α agents or other biologic therapies remains.

SUMMARY OF THE DISCLOSURE

The present disclosure addresses the above needs and provides methodsfor treating Crohn's disease and ulcerative colitis. In some aspects,the present disclosure provides methods for treating Crohn's disease inpatients that have moderately to severely active Crohn's disease. Insome aspects, the present disclosure provides methods for treatingulcerative colitis in patients that have moderately to severely activeulcerative colitis. The patient may have had an inadequate response toor experienced intolerance to conventional treatment, such asaminosalicylates, corticosteroids or immunosuppressants, or to aprevious treatment with an anti-TNF therapy or another biologic agent.In one embodiment, the patient is an adult with moderately to severelyactive Crohn's disease and has had an inadequate response to, or wereintolerant to, corticosteroid, immunomodulator, or biologic therapy.

In one embodiment, the present disclosure is directed to a method ofinducing clinical remission of Crohn's disease in a patient, said methodcomprising: a) administering to the patient at least one induction doseof(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(upadacitinib), or a pharmaceutically acceptable salt or solid stateform thereof, wherein said induction dose comprises 30 to 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the method further comprises maintaining theclinical remission of Crohn's disease, wherein the method furthercomprises b) administering a first maintenance dose of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose once dailythereafter.

In another embodiment, the present disclosure is directed to a method ofinducing endoscopic improvement of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient at least oneinduction dose of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, wherein said induction dose comprises 30 to 45mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, the method further comprisesmaintaining the endoscopic improvement of Crohn's disease, wherein themethod further comprises b) administering a first maintenance dose ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof to the patient after the last induction dose is administered;and c) administering at least one additional maintenance dose once dailythereafter.

In another embodiment, the present disclosure is directed to a method ofinducing clinical remission of Crohn's disease in a patient, said methodcomprising: a) administering to the patient at least one induction doseof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, wherein said induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable or solid state form saltthereof. In one embodiment, the method further comprises maintaining theclinical remission of Crohn's disease, wherein the method furthercomprises b) administering a first maintenance dose of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose once dailythereafter.

In another embodiment, the present disclosure is directed to a method ofinducing endoscopic remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient at least oneinduction dose of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, wherein said induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the method further comprises maintaining theendoscopic remission of Crohn's disease, wherein the method furthercomprises b) administering a first maintenance dose of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose once dailythereafter.

In one embodiment, the induction dose comprises 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with a corticosteroid,an immunosuppressant, or a biologic agent. In one embodiment, thepatient had an inadequate response to or experienced intolerance to aprevious treatment with an anti-TNF agent. In one embodiment, thepatient had moderately to severely active Crohn's disease prior toadministration of the induction dose.

In one embodiment, the induction dose is administered orally to thepatient. In one embodiment, the induction dose is administered oncedaily to the patient.

In one embodiment, clinical remission is achieved within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, clinicalremission is achieved within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, endoscopic improvement is achieved within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment,endoscopic improvement is achieved within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, clinical remission is achieved within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, clinicalremission is achieved within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, endoscopic remission is achieved within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment,endoscopic remission is achieved within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, after administration of at least one induction dose,the patient's Simplified Endoscopic Score for Crohn's Disease (SES-CD)is greater than a 50% decrease or endoscopic remission versus thepatient's baseline SES-CD. In one embodiment, after administration of atleast one induction dose, the patient's Simplified Endoscopic Score forCrohn's Disease (SES-CD) is at least a 2 point reduction versus thepatient's baseline SES-CD. In one embodiment, after administration of atleast one induction dose, the patient achieves an endoscopic remission.In one embodiment, after administration of at least one induction dose,the patient achieves a clinical response. In one embodiment, the patientachieves a clinical response as early as two weeks from the firstinduction dose. In one embodiment, after administration of at least oneinduction dose, the patient achieves a CDAI score of less than 150.

In one embodiment, the first maintenance dose comprises 15 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the first maintenance dose comprises 30 mgof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof.

In one embodiment, the at least one additional maintenance dosecomprises 15 mg of upadacitinib, or a pharmaceutically acceptable saltor solid state form thereof. In one embodiment, the at least oneadditional maintenance dose comprises 30 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the first maintenance dose and said at least oneadditional maintenance dose are administered orally. In one embodiment,the first maintenance dose and said at least one additional maintenancedose are administered once daily.

In one embodiment, the patient maintains clinical remission. In oneembodiment, the patient maintains endoscopic improvement. In oneembodiment, the patient maintains endoscopic remission.

In one embodiment, the patient maintains a Simplified Endoscopic Scorefor Crohn's Disease (SES-CD) that is greater than a 50% decrease orendoscopic remission versus the patient's baseline SES-CD. In oneembodiment, the said patient maintains a Simplified Endoscopic Score forCrohn's Disease (SES-CD) that is at least a 2 point reduction versus thepatient's baseline SES-CD. In one embodiment, the patient maintains anendoscopic remission. In one embodiment, the patient maintains a CDAIscore of less than 150. In one embodiment, the patient maintains aclinical response.

In one embodiment, the patient achieves a CDAI score of less than 150before administration of the first maintenance dose. In one embodiment,the patient achieves a clinical response before administration of thefirst maintenance dose.

In one embodiment, the induction dose comprises 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof,administered orally once daily, the first maintenance dose comprises 30mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, administered orally once daily, and the at least oneadditional maintenance dose comprises 30 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof,administered orally once daily.

In one embodiment, the induction dose comprises 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof,administered orally once daily, the first maintenance dose comprises 15mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, administered orally once daily, and the at least oneadditional maintenance dose comprises 15 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof,administered orally once daily.

In one embodiment, the induction dose is in a once-daily, modifiedrelease formulation. In one embodiment, the first maintenance dose andthe at least one additional maintenance dose are each in a once-daily,modified release formulation.

In one embodiment, the present disclosure is directed to a method fortreating Crohn's disease comprising administering to a patient 15 mg to45 mg of upadacitinib, or a pharmaceutically acceptable salt or solidstate form thereof. In one embodiment, the method comprisingadministering 15 mg of upadacitinib, or a pharmaceutically acceptablesalt or solid state form thereof. In one embodiment, the methodcomprising administering 30 mg of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, themethod comprising administering 45 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, upadacitinib, or a pharmaceutically acceptable salt or solidstate form thereof is administered orally to the patient. In oneembodiment, upadacitinib, or a pharmaceutically acceptable salt or solidstate form thereof is administered once daily to the patient.

In one embodiment, the present disclosure is directed to a method fortreating Crohn's disease comprising: a) administering to a patient atleast one induction dose of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, wherein said induction dosecomprises 45 mg of upadacitinib, or a pharmaceutically acceptable saltor solid state form thereof. In one embodiment, the method furthercomprises b) administering a first maintenance dose of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose to the patientonce daily thereafter.

In one such embodiment, the first maintenance dose comprises 15 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the first maintenance dose comprises 30 mgof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, the first maintenance dose isadministered orally.

In one embodiment, the at least one additional maintenance dosecomprises 15 mg of upadacitinib, or a pharmaceutically acceptable saltor solid state form thereof. In one embodiment, the at least oneadditional maintenance dose comprises 30 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the at least one additional maintenance dose is administeredorally.

In one embodiment, the patient maintains a CDAI score of less than 150.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with a corticosteroid,an immunosuppressant, or a biologic agent. In one embodiment, thepatient had an inadequate response to or experienced intolerance to aprevious treatment with an anti-TNF agent.

In one embodiment, the patient achieves a clinical remission afteradministration of at least one induction dose. In one embodiment, thepatient achieves an endoscopic improvement after administration of atleast one induction dose. In one embodiment, the patient achieves anendoscopic remission after administration of at least one inductiondose. In one embodiment, the patient achieves a clinical response afteradministration of at least one induction dose.

In one embodiment, the induction dose comprises 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof,administered orally once daily, said first maintenance dose comprises 30mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, administered orally once daily, and said at least oneadditional maintenance dose comprises 30 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof,administered orally once daily.

In one embodiment, the induction dose comprises 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof,administered orally once daily, said first maintenance dose comprises 15mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, administered orally once daily, and said at least oneadditional maintenance dose comprises 15 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof,administered orally once daily.

In one embodiment, the induction dose is in a once-daily, modifiedrelease formulation. In one embodiment, the first maintenance dose andthe at least one additional maintenance dose are each in a once-daily,modified release formulation. In one embodiment, the patient hadmoderately to severely active Crohn's disease prior to administration ofthe induction dose.

In one embodiment, the present disclosure is directed to a method ofinducing remission in a patient having moderately to severely activeCrohn's disease, the method comprising administering 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof, to the patient. In one such embodiment, the patient had aninadequate response to or was intolerant to aminosalicylates,corticosteroids, immunosuppressants, biologic agents, anti-TNF agents,or combinations thereof.

In one embodiment, the present disclosure is directed to a method ofinducing clinical remission in a patient having moderately to severelyactive Crohn's disease the method comprising administering 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof, to the patient. In one such embodiment, the patient had aninadequate response to or was intolerant to aminosalicylates,corticosteroids, immunosuppressants, biologic agents, anti-TNF agents,or combinations thereof.

In one embodiment, the present disclosure is directed to a method ofinducing endoscopic improvement in a patient having moderately toseverely active Crohn's disease the method comprising administering 45mg of upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof to the patient. In one such embodiment, the patient had aninadequate response to or was intolerant to aminosalicylates,corticosteroids, immunosuppressants, biologic agents, anti-TNF agents,or combinations thereof.

In one embodiment, the present disclosure is directed to a method oftreating a refractory patient having moderately to severely activeCrohn's disease the method comprising administering 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, to the patient. In one such embodiment, clinical remission isinduced within 16 weeks of administering the initial dose ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one such embodiment, endoscopic improvement is inducedwithin 12 weeks or within 16 weeks of administering the initial dose ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, the induction dose comprises 45 mg of upadacitinib ora pharmaceutically acceptable salt or solid state form thereof. Inanother embodiment, the first maintenance dose and/or the at least oneadditional maintenance doses comprise 15 mg to 30 mg of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof.

In another embodiment, the method of the present disclosure is a methodof inducing clinical remission of Crohn's disease in a patient, themethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical remission within 12 weeks ofadministration of the first induction dose.

In one embodiment, clinical remission of Crohn's disease is inducedwithin 4 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In another embodiment, the method is a method of inducing clinicalresponse of Crohn's disease in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 2 weeks and comprises 45 mgof upadacitinib or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves clinical response.

In one embodiment, the clinical response of Crohn's disease is inducedwithin 4 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof. In one embodiment, theclinical response of Crohn's disease is induced within 12 weeks of thefirst induction dose of upadacitinib, or a pharmaceutically acceptablesalt thereof.

In another embodiment, the method is a method of inducing endoscopicremission of Crohn's disease in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 12 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves endoscopic remission within 12 weeks of administration of thefirst induction dose.

In one embodiment, the endoscopic remission of Crohn's disease isinduced within 4 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the endoscopic remission of Crohn's disease isinduced within 12 weeks of the first induction dose of upadacitinib, ora pharmaceutically acceptable salt thereof.

In another embodiment, the method is a method of inducing endoscopicresponse of Crohn's disease in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 12 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves endoscopic response within 12 weeks of administration of thefirst induction dose.

In one embodiment, the endoscopic response of Crohn's disease is inducedwithin 12 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In another embodiment, the method is a method of inducingcorticosteroid-free remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 12weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves steroid-free remission within 4 weeks ofadministration of the first induction dose.

In one embodiment, the patient is an adult with moderately to severelyactive Crohn's disease.

In one embodiment, the patient experiences a CDAI reduction of greaterthan 150 within 12 weeks of administration of the first induction dose.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with a corticosteroid,an immunosuppressant, or a biologic agent.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to an infliximab, adalimumab or certolizumabpegol.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to an anti-integrin or an anti-IL12/23. In oneembodiment, the patient had an inadequate response to or experiencedintolerance to vedolizumab, natalizumab, or ustekinumab.

In one embodiment, the patient has had a diagnosis of Crohn's diseasefor more than ten years and has had an inadequate response to orexperienced intolerance to one or more previous treatments. In oneembodiment, the previous treatments are selected from the groupconsisting of corticosteroids, immunosuppressants, antibiotics andbiologic therapies.

In one embodiment, the method comprises a method of inducing andmaintaining clinical remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 12 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method comprises a method of inducing andmaintaining clinical response of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 2weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical response within 2 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof, and e) wherein saidpatient maintains clinical response for 52 weeks after administration ofthe first induction dose.

In one embodiment, the clinical response of Crohn's disease is inducedwithin 4 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the clinical response of Crohn's disease is inducedwithin 12 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the method comprises a method of inducing andmaintaining endoscopic remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof, and b)wherein said patient achieves endoscopic remission within 12 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains endoscopic remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the endoscopic remission of Crohn's disease isinduced within 12 weeks of the first induction dose of upadacitinib, ora pharmaceutically acceptable salt thereof.

In one embodiment, the method is a method of inducing and maintainingendoscopic response of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic response within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains endoscopic response for 52 weeks after administrationof the first induction dose.

In one embodiment, the endoscopic response of Crohn's disease is inducedwithin 12 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the method is a method of inducing and maintainingcorticosteroid-free remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 12weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves steroid-free remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered and; d)administering at least one additional maintenance dose to the patient ofupadacitinib, or a pharmaceutically acceptable salt thereof; and e)wherein said patient maintains corticosteroid-free remission for 52weeks after administration of the first induction dose.

In one embodiment, the patient is an adult with moderately to severelyactive Crohn's disease.

In one embodiment, the patient experiences improvement in stoolfrequency one week after the first induction dose. In one embodiment thepatient experiences improvement in abdominal pain at 8 weeks after thefirst induction dose.

In one embodiment, the patient experiences a CDAI reduction of greaterthan 150 within 12 weeks of administration of the first induction dose.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with a corticosteroid,an immunosuppressant, or a biologic agent.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the anti-TNF agent is infliximab, adalimumab orcertolizumab pegol.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to an anti-integrin or an anti-IL12/23. In oneembodiment, the patient had an inadequate response to or experiencedintolerance to vedolizumab, natalizumab, or ustekinumab.

In one embodiment, the patient has had a diagnosis of Crohn's diseasefor more than ten years and has had an inadequate response to orexperienced intolerance to a previous treatment.

In one embodiment, the previous treatments are selected fromcorticosteroids, immunosuppressants, antibiotics and biologic therapies.

In one embodiment, the method is a method of inducing and maintainingclinical remission of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical response of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 2weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical response within 2 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said maintenance dose is administeredorally once a day and comprises 15 mg of upadacitinib, or a 15 mg freebase equivalent amount of a pharmaceutically acceptable salt thereofafter the last induction dose is administered; d) administering at leastone additional maintenance dose to the patient of upadacitinib, or apharmaceutically acceptable salt thereof, and e) wherein said patientmaintains clinical response for 52 weeks after administration of thefirst induction dose.

In one embodiment, the clinical response of Crohn's disease is inducedwithin 4 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the clinical response of Crohn's disease is inducedwithin 12 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the method is a method of inducing and maintainingendoscopic remission of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains endoscopic remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingendoscopic remission of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 12weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains endoscopic remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the endoscopic remission of Crohn's disease isinduced within 12 weeks of the first induction dose of upadacitinib, ora pharmaceutically acceptable salt thereof.

In one embodiment, the method is a method of inducing and maintainingendoscopic response of Crohn's disease in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic response within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said maintenance dose is administeredorally once a day and comprises 15 mg of upadacitinib, or a 15 mg freebase equivalent amount of a pharmaceutically acceptable salt thereofafter the last induction dose is administered; d) administering at leastone additional maintenance dose to the patient of upadacitinib, or apharmaceutically acceptable salt thereof; and e) wherein said patientmaintains endoscopic response for 52 weeks after administration of thefirst induction dose.

In one embodiment, the endoscopic response of Crohn's disease is inducedwithin 12 weeks of the first induction dose of upadacitinib, or apharmaceutically acceptable salt thereof.

In one embodiment, the method is a method of inducing and maintainingcorticosteroid-free remission of Crohn's disease in a patient, saidmethod comprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 12weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves steroid-free remission within 12 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered and; d)administering at least one additional maintenance dose to the patient ofupadacitinib, or a pharmaceutically acceptable salt thereof; and e)wherein said patient maintains corticosteroid-free remission for 52weeks after administration of the first induction dose.

In one embodiment, the patient is an adult with moderately to severelyactive Crohn's disease.

In one embodiment, the patient experiences a CDAI reduction of >150within 12 weeks of administration of the first induction dose.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with a corticosteroid,an immunosuppressant, or a biologic agent.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to a previous treatment anti-TNF agent isinfliximab, adalimumab or certolizumab pegol.

In one embodiment, the patient had an inadequate response to orexperienced intolerance to an anti-integrin or an anti-IL12/23. In oneembodiment, the patient had an inadequate response to or experiencedintolerance to vedolizumab, natalizumab, or ustekinumab.

In one embodiment, the patient has had a diagnosis of Crohn's diseasefor more than ten years and has had an inadequate response to orexperienced intolerance to one or more previous treatment.

In one embodiment, the method comprises a method wherein the previoustreatments are selected from corticosteroids, immunodulators,antibiotics and biologic therapies.

In one embodiment, the method is a method of inducing clinical remissionof Crohn's disease in an adult patient having moderately to severelyactive Crohn's disease, the method comprising orally administering oncedaily to the patient a 45 mg dose of upadacitinib, wherein the patientachieves clinical remission per Crohn's Disease Activity Index (CDAI) at12 weeks after the first daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.

In one embodiment, the biologic therapy comprises an anti-TNF agent.

In one embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23.

In one embodiment, the biologic therapy comprises vedolizumab,natalizumab, or ustekinumab.

In one embodiment, the method is a method of inducing clinical remissionof Crohn's disease in an adult patient having moderately to severelyactive Crohn's disease, the method comprising orally administering oncedaily to the patient a 45 mg dose of upadacitinib, wherein the patientachieves clinical remission patient reported outcomes (PROs) at 12 weeksafter the first daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.

In one embodiment, the biologic therapy comprises an anti-TNF agent.

In one embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23.

In one embodiment, the biologic therapy comprises vedolizumab,natalizumab, or ustekinumab.

In one embodiment, the method is a method of inducing clinical remissionof Crohn's disease in an adult patient having moderately to severelyactive Crohn's disease, the method comprising orally administering oncedaily to the patient a 45 mg dose of upadacitinib, wherein the patientachieves clinical remission per patient reported outcomes (PROs) at 4weeks after the first daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.

In one embodiment, the biologic therapy comprises an anti-TNF agent.

In one embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23.

In one embodiment, the biologic therapy comprises vedolizumab,natalizumab, or ustekinumab.

In one embodiment, the method is a method of inducing endoscopicresponse of Crohn's disease in an adult patient having moderately toseverely active Crohn's disease, the method comprising orallyadministering once daily to the patient a 45 mg dose of upadacitinib,wherein the patient achieves endoscopic response at 12 weeks after thefirst daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.

In one embodiment, the biologic therapy comprises an anti-TNF agent.

In one embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23.

In one embodiment, the biologic therapy comprises vedolizumab,natalizumab, or ustekinumab.

In one embodiment, the method is a method of inducing endoscopicremission of Crohn's disease in an adult patient having moderately toseverely active Crohn's disease, the method comprising orallyadministering once daily to the patient a 45 mg dose of upadacitinib,wherein the patient achieves endoscopic remission at 12 weeks after thefirst daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.

In one embodiment, the biologic therapy comprises an anti-TNF agent.

In one embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23.

In one embodiment, the biologic therapy comprises vedolizumab,natalizumab, or ustekinumab.

In one embodiment, the method comprises inducing clinical remission ofulcerative colitis in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 4 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves clinical remission within 4 weeks of administration of thefirst induction dose.

In one embodiment, the method comprises inducing clinical remission ofulcerative colitis in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 6 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves clinical remission within 6 weeks of administration of thefirst 45 mg induction dose.

In one embodiment, the method comprises inducing clinical remission ofulcerative colitis in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves clinical remission within 8 weeks of administration of thefirst 45 mg induction dose.

In one embodiment, the method comprises a method of inducing endoscopicimprovement of ulcerative colitis in a patient, said method comprising:a) administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves endoscopic improvement within 8 weeks of administration of thefirst induction dose.

In one embodiment, the method comprises a method of inducing endoscopicremission of ulcerative colitis in a patient, said method comprising: a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves endoscopic remission within 8 weeks of administration of thefirst 45 mg induction dose.

In one embodiment, the patient has moderately to severely activeulcerative colitis.

In one embodiment, the patient is taking corticosteroids at the time ofthe first induction dose.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In one embodiment, the patient is unable to taper corticosteroid below adose equivalent to prednisone 10 mg daily orally without recurrentactive disease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced signs and symptoms of persistently activedisease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In one embodiment, the patient experiencing the inadequate response tobiologic therapies experienced signs and symptoms of persistently activedisease despite a history of a) at least one 6-week induction regimen ofinfliximab comprising a ≥5 mg/kg intravenous dose at 0, 2 and 6 weeks;b) at least one 4-week induction regimen of adalimumab comprising one160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose atleast two weeks apart; c) at least one 2-week induction regimen ofgolimumab comprising one 200 mg subcutaneous dose followed by one 100 mgsubcutaneous dose at least 2 weeks apart); d) at least one 6-weekinduction regimen of vedolizumab comprising a 300 mg intravenous dose at0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In one embodiment, the patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure or infection.

In one embodiment, the method is a method of inducing clinical remissionof ulcerative colitis in a patient, said method comprising: (a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for up to 16 weeks and comprises 45 mg ofupadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and (b) wherein said patientachieves clinical remission within 16 weeks of administration of thefirst induction dose.

In one embodiment, the method is a method of of inducing clinicalremission of ulcerative colitis in a patient, said method comprising:(a) administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day and comprises 45 mg of upadacitinib, or a45 mg free base equivalent amount of a pharmaceutically acceptable saltthereof; and (b) continuing the administering until said patientachieves clinical remission.

In one embodiment, the clinical remission is defined by an Adapted Mayoscore ≤2.

In one embodiment, the method comprises an SFS≤1 and not greater thanbaseline, a RBS of 0, and an endoscopic subscore ≤1.

In one embodiment, the clinical remission is achieved after more than 8weeks, but within 16 weeks of administration of the first 45 mginduction dose.

In one embodiment, the method is a method of inducing inducing clinicalremission of ulcerative colitis, said method comprising: (a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and (b) wherein the patientachieves clinical response within 8 weeks of administration of the first45 mg induction dose, wherein the patient was previously treated with 45mg of upadacitinib for at least 8 weeks and did not exhibit a clinicalresponse.

In one embodiment, the method is a method of inducing clinical responsein a patient having ulcerative colitis, said method comprising: (a)administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and (b) wherein the patientachieves clinical response within 8 weeks of administration of the first45 mg induction dose, wherein the patient was previously treated with 45mg of upadacitinib for at least 8 weeks and did not exhibit a clinicalresponse.

In one embodiment, the present disclosure is directed to a method ofinducing a clinical response in a patient with moderately to severelyactive ulcerative colitis, said method comprising: a) administering tothe patient at least one induction dose of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, whereinsaid induction dose comprises 45 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof.

In one such embodiment, the clinical response is a clinical response iswherein the patient has a decrease from a baseline Adapted Mayo scoregreater than or equal to 2 points and greater than or equal to 30%accompanied by a decrease in rectal bleeding subscore of greater than orequal to 1 or an absolute rectal bleeding subscore of 0 or 1.

In another such embodiment, the clinical response is a clinical responseis wherein the patient has a decrease from a baseline Full Mayo scoregreater than or equal to 3 points and greater than or equal to 30%accompanied by a decrease in rectal bleeding subscore from baseline ofgreater than or equal to 1 or an absolute rectal bleeding subscore of 0or 1.

In yet another embodiment, the method further comprising maintaining theclinical response, said method further comprising: b) administering afirst maintenance dose of upadacitinib, or a pharmaceutically acceptablesalt or solid state form thereof to the patient after the last inductiondose is administered; and c) administering at least one additionalmaintenance dose once daily thereafter.

In another embodiment, the induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In another embodiment, the first maintenance dose and/or the atleast one additional maintenance dose comprises 15 mg to 30 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 4 weeks ofadministration of the first induction dose) administering to the patienta first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 30 mg of upadacitinib, or a30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 6weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 6 weeks ofadministration of the first 45 mg induction dose; and c) administeringto the patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 30 mg ofupadacitinib, or a 30 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 30 mg ofupadacitinib, or a 30 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the method is inducing and maintaining endoscopicimprovement of ulcerative colitis in a patient, said method comprising:a) administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and b) wherein said patientachieves endoscopic improvement within 8 weeks of administration of thefirst induction dose; c) administering to the patient a firstmaintenance dose of upadacitinib, or a pharmaceutically acceptable saltthereof, wherein said first maintenance dose is administered orally oncea day and comprises 30 mg of upadacitinib, or a 30 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof afterthe last induction dose is administered; d) administering at least oneadditional maintenance dose to the patient of upadacitinib, or apharmaceutically acceptable salt thereof; and e) wherein said patientmaintains clinical remission for 52 weeks after administration of thefirst induction dose.

In one embodiment, the method comprises inducing and maintainingendoscopic remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 30 mg ofupadacitinib, or a 30 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the method comprises inducing and maintainingendoscopic remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 15 mg ofupadacitinib, or a 15 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the patient has moderately to severely activeulcerative colitis. In one embodiment the patient is an adult. In oneembodiment, the patient has had an inadequate response corticosteroid,immunomodulatory or biologic therapy. In one embodiment, the patient hashad loss of response to aminosalicylate, corticosteroid,immunomodulatory or biologic therapy. In one embodiment, the patient wasintolerant to corticosteroid, immunomodulatory or biologic therapy. Inone embodiment, the patient is an adult and has moderately to severelyactive ulcerative colitis and has had an inadequate response to, loss ofresponse to, or was intolerant to aminosalicylate, corticosteroid,immunomodulatory (IMM), or biologic therapy.

In one embodiment, the patient is taking corticosteroids at the time ofthe first induction dose.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In one embodiment, the patient is unable to taper corticosteroid below adose equivalent to prednisone 10 mg daily orally without recurrentactive disease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced signs and symptoms of persistently activedisease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In one embodiment, the ulcerative colitis patient experiencing theinadequate response to biologic therapies experienced signs and symptomsof persistently active disease despite a history of a) at least one6-week induction regimen of infliximab comprising a ≥5 mg/kg intravenousdose at 0, 2 and 6 weeks; b) at least one 4-week induction regimen ofadalimumab comprising one 160 mg subcutaneous dose followed by one 80 mgsubcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mgsubcutaneous dose at least two weeks apart; c) at least one 2-weekinduction regimen of golimumab comprising one 200 mg subcutaneous dosefollowed by one 100 mg subcutaneous dose at least 2 weeks apart; d) atleast one 6-week induction regimen of vedolizumab comprising a 300 mgintravenous dose at 0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In one embodiment, the patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure or infection.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 6weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 6 weeks ofadministration of the first 45 mg induction dose; and c) administeringto the patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said maintenance doseis administered orally once a day and comprises 15 mg of upadacitinib,or a 15 mg free base equivalent amount of a pharmaceutically acceptablesalt thereof after the last induction dose is administered; d)administering at least one additional maintenance dose to the patient ofupadacitinib, or a pharmaceutically acceptable salt thereof; and e)wherein said patient maintains clinical remission for 52 weeks afteradministration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 15 mg ofupadacitinib, or a 15 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingendoscopic improvement of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic improvement within 8 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains endoscopic improvement for 52 weeks afteradministration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingendoscopic remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 15 mg ofupadacitinib, or a 15 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains endoscopic remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the patient has moderately to severely activeulcerative colitis.

In one embodiment, the patient is taking corticosteroids at the time ofthe first induction dose.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In one embodiment, the patient is unable to taper corticosteroid below adose equivalent to prednisone 10 mg daily orally without recurrentactive disease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced signs and symptoms of persistently activedisease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.

In one embodiment, the patient experiencing the intolerance toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In one embodiment, the patient experiencing the inadequate response tobiologic therapies experienced signs and symptoms of persistently activedisease despite a history of a) at least one 6-week induction regimen ofinfliximab comprising a ≥5 mg/kg intravenous dose at 0, 2 and 6 weeks;b) at least one 4-week induction regimen of adalimumab comprising one160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose atleast two weeks apart; c) at least one 2-week induction regimen ofgolimumab comprising one 200 mg subcutaneous dose followed by one 100 mgsubcutaneous dose at least 2 weeks apart; d) at least one 6-weekinduction regimen of vedolizumab comprising a 300 mg intravenous dose at0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In one embodiment, the patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure or infection.

In one embodiment, the method is a method of maintaining clinicalremission of ulcerative colitis in a patient, said method comprising:administering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 30 mgof upadacitinib, or a 30 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsclinical remission.

In one embodiment, the method is a method of maintaining endoscopicimprovement of ulcerative colitis in a patient, said method comprising:administering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 30 mgof upadacitinib, or a 30 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsendoscopic improvement.

In one embodiment, the method is a method of maintaining endoscopicremission of ulcerative colitis in a patient, said method comprising:administering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 30 mgof upadacitinib, or a 30 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsendoscopic remission.

In one embodiment, the method is a method of maintaining clinicalremission of ulcerative colitis in a patient, said method comprising:administering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 15 mgof upadacitinib, or a 15 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsclinical remission.

In one embodiment, the method is a method of maintaining endoscopicimprovement of ulcerative colitis in a patient, said method comprisingadministering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 15 mgof upadacitinib, or a 15 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsendoscopic improvement.

In one embodiment, the method is a method of maintaining endoscopicremission of ulcerative colitis in a patient, said method comprising:administering to the patient a daily maintenance dose of upadacitinib,or a pharmaceutically acceptable salt thereof, wherein said dailymaintenance dose is administered orally once a day and comprises 15 mgof upadacitinib, or a 15 mg free base equivalent amount of thepharmaceutically acceptable salt thereof; wherein said patient maintainsendoscopic remission.

In one embodiment, the patient has moderately to severely activeulcerative colitis.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is maintained for at least 52 weeks.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants, or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In one embodiment, the said patient is unable to taper corticosteroidbelow a dose equivalent to prednisone 10 mg daily orally withoutrecurrent active disease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection.

In one embodiment, the said patient experiencing the inadequate responseto immunosuppressants experienced signs and symptoms of persistentlyactive disease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.

In one embodiment, the patient experiencing intolerance toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In one embodiment, the patient experiencing the inadequate response tobiologic therapies experienced signs and symptoms of persistently activedisease despite a history of: at least one 6-week induction regimen ofinfliximab comprising a greater than or equal to 5 mg/kg intravenousdose at 0, 2 and 6 weeks; at least one 4-week induction regimen ofadalimumab comprising one 160 mg subcutaneous dose followed by one 80 mgsubcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mgsubcutaneous dose at least two weeks apart; at least one 2-weekinduction regimen of golimumab comprising one 200 mg subcutaneous dosefollowed by one 100 mg subcutaneous dose at least 2 weeks apart; or atleast one 6-week induction regimen of vedolizumab comprising a 300 mgintravenous dose at 0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In one embodiment, the patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure of infection.

In one embodiment, the clinical remission is defined by an Adapted Mayoscore ≤2.

In one embodiment, the method comprises an SFS≤1 and not greater thanbaseline, a RBS of 0, and an endoscopic subscore ≤1.

In one embodiment, the clinical remission is defined by an Adapted Mayoscore ≤2, and is corticosteroid free.

In one embodiment, the patient has been corticosteroid free for 90 daysor more immediately preceding week 52 of daily maintenance doseadministration.

In one embodiment, the patient exhibits a Histologic Endoscopic MucosalImprovement (HEMI) comprising an endoscopic score ≤1 and a Geboes score≤3.1 at week 52.

In one embodiment, the patient exhibits mucosal healing comprising anendoscopic score of 0 and a Geboes score <2 at week 52.

In one embodiment, the patient does not exhibit bowel urgency at week52.

In one embodiment, the patient does not exhibit abdominal pain at week52.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 4weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 4 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 6weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; b)wherein said patient achieves clinical remission within 6 weeks ofadministration of the first 45 mg induction dose; and c) administeringto the patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said maintenance doseis administered orally once a day and comprises 15 mg of upadacitinib,or a 15 mg free base equivalent amount of a pharmaceutically acceptablesalt thereof after the last induction dose is administered; d)administering at least one additional maintenance dose to the patient ofupadacitinib, or a pharmaceutically acceptable salt thereof; and e)wherein said patient maintains clinical remission for 52 weeks afteradministration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingclinical remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves clinical remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 15 mg ofupadacitinib, or a 15 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the method is a method of inducing and maintainingendoscopic improvement of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic improvement within 8 weeks ofadministration of the first induction dose; c) administering to thepatient a first maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day and comprises 15 mg of upadacitinib, or a15 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; d) administeringat least one additional maintenance dose to the patient of upadacitinib,or a pharmaceutically acceptable salt thereof; and e) wherein saidpatient maintains clinical remission for 52 weeks after administrationof the first induction dose.

In one embodiment, the method is a method of inducing and maintainingendoscopic remission of ulcerative colitis in a patient, said methodcomprising: a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and b)wherein said patient achieves endoscopic remission within 8 weeks ofadministration of the first 45 mg induction dose; c) administering tothe patient a first maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day and comprises 15 mg ofupadacitinib, or a 15 mg free base equivalent amount of apharmaceutically acceptable salt thereof after the last induction doseis administered; d) administering at least one additional maintenancedose to the patient of upadacitinib, or a pharmaceutically acceptablesalt thereof; and e) wherein said patient maintains clinical remissionfor 52 weeks after administration of the first induction dose.

In one embodiment, the patient has moderately to severely activeulcerative colitis.

In one embodiment, the patient is taking corticosteroids at the time ofthe first induction dose.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In one embodiment, the patient is unable to taper corticosteroid below adose equivalent to prednisone 10 mg daily orally without recurrentactive disease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced signs and symptoms of persistently activedisease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.

In one embodiment, the patient experiencing the intolerance toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In one embodiment, the patient experiencing the inadequate response tobiologic therapies experienced signs and symptoms of persistently activedisease despite a history of a) at least one 6-week induction regimen ofinfliximab comprising a ≥5 mg/kg intravenous dose at 0, 2 and 6 weeks;b) at least one 4-week induction regimen of adalimumab comprising one160 mg subcutaneous dose followed by one 80 mg subcutaneous dose or one80 mg subcutaneous dose, followed by one 40 mg subcutaneous dose atleast two weeks apart; c) at least one 2-week induction regimen ofgolimumab comprising one 200 mg subcutaneous dose followed by one 100 mgsubcutaneous dose at least 2 weeks apart; d) at least one 6-weekinduction regimen of vedolizumab comprising a 300 mg intravenous dose at0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In one embodiment, the patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure or infection. In some embodiments, the methodis a method of inducing Histologic Endoscopic Mucosal Improvement (HEMI)in a patient with ulcerative colitis, said method comprising:administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and wherein said patientachieves Histologic Endoscopic Mucosal Improvement (HEMI) comprising anendoscopic score ≤1 and a Geboes score ≤3.1 within 8 weeks ofadministration of the induction dose.

In some embodiments, the method is a method of inducing and maintainingHistologic Endoscopic Mucosal Improvement (HEMI) in a patient withulcerative colitis, said method comprising: administering to the patientan induction dose of upadacitinib, or a pharmaceutically acceptable saltthereof, wherein said induction dose is administered orally once a dayfor at least 8 weeks and comprises 45 mg of upadacitinib, or a 45 mgfree base equivalent amount of a pharmaceutically acceptable saltthereof; wherein said patient achieves Histologic Endoscopic MucosalImprovement (HEMI) comprising an endoscopic score ≤1 and a Geboes score≤3.1 within 8 weeks of administration of the first induction dose;administering to the patient a maintenance dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said first maintenancedose is administered orally once a day for at least 52 weeks andcomprises 15 mg of upadacitinib or 30 mg of upadacitinib, or a 15 mg or30 mg free base equivalent amount of a pharmaceutically acceptable saltthereof after the last induction dose is administered; wherein saidpatient maintains Histologic Endoscopic Mucosal Improvement (HEMI)comprising an endoscopic score ≤1 and a Geboes score ≤3.1 for 52 weeksafter administration of the first maintenance dose.

In some embodiments, the method is a method of maintaining HistologicEndoscopic Mucosal Improvement (HEMI) in a patient with ulcerativecolitis, said method comprising: administering to the patient amaintenance dose of upadacitinib, or a pharmaceutically acceptable saltthereof, wherein said first maintenance dose is administered orally oncea day for at least 52 weeks and comprises 15 mg of upadacitinib or 30 mgof upadacitinib, or a 15 mg or 30 mg free base equivalent amount of apharmaceutically acceptable salt thereof; wherein said patient maintainsHistologic Endoscopic Mucosal Improvement (HEMI) comprising anendoscopic score ≤1 and a Geboes score ≤3.1 for 52 weeks afteradministration of the first maintenance dose.

In one embodiment, the ulcerative colitis or Crohn's disease patientexperiencing the inadequate response to biologic therapies experiencedsigns and symptoms of persistently active disease despite a history ofa) at least one 6-week induction regimen of infliximab comprising a ≥5mg/kg intravenous dose at 0, 2 and 6 weeks; b) at least one 4-weekinduction regimen of adalimumab comprising one 160 mg subcutaneous dosefollowed by one 80 mg subcutaneous dose or one 80 mg subcutaneous dose,followed by one 40 mg subcutaneous dose at least two weeks apart; c) atleast one 2-week induction regimen of golimumab comprising one 200 mgsubcutaneous dose followed by one 100 mg subcutaneous dose at least 2weeks apart; d) at least one 6-week induction regimen of vedolizumabcomprising a 300 mg intravenous dose at 0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit. In one embodiment,the patient experiencing intolerance to biologic therapies experiencedinfusion-related reaction, demyelination, congestive heart failure orinfection.

In one embodiment, the method is a method of treating Crohn's disease inan adult patient having moderately to severely active Crohn's disease,the method comprising: a. orally administering to the patient aninduction dose of 45 mg of upadacitinib once daily for 12 weeks; and b.orally administering to the patient, after the last induction dose of 45mg of upadacitinib, a maintenance dose of 15 mg of upadacitinib oncedaily.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 12 weeks after the administration ofthe initial induction dose of 45 mg of upadacitinib.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 52 weeks after the administration ofthe initial maintenance dose of 15 mg of upadacitinib.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiments, the method is a method of treating Crohn's diseasein an adult patient having refractory or severely active Crohn'sdisease, the method comprising: a) orally administering to the patientan induction dose of 45 mg of upadacitinib once daily for 12 weeks; andb) orally administering to the patient, after the last induction dose of45 mg of upadacitinib, a maintenance dose of 30 mg of upadacitinib oncedaily.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 12 weeks after the administration ofthe initial induction dose of 45 mg of upadacitinib.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 52 weeks after the administration ofthe initial maintenance dose of 30 mg of upadacitinib.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiments, the method is a method of treating an adult patientsuffering from moderately to severely active Crohn's disease that isstatistically significantly superior to placebo, comprising orallyadministering once daily to the patient an induction dose of 45 mg ofupadacitinib once daily for 12 weeks, wherein when the method is used totreat a population of human patients suffering from moderately toseverely active Crohn's disease, a statistically significantly greaterpercentage of patients achieve clinical remission per Crohn's DiseaseActivity Index (CDAI) at 12 weeks after the administration of theinitial induction dose of 45 mg of upadacitinib compared to a controlgroup of human patients treated with placebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the method further comprises orally administering tothe patient, after the last induction dose of 45 mg of upadacitinib, amaintenance dose of 15 mg of upadacitinib once daily, wherein astatistically significantly greater percentage of patients achieveclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 15 mg ofupadacitinib compared to a control group of human patients treated withplacebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the adult patient is suffering from refractory orseverely active Crohn's disease and the method further comprises orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 30mg of upadacitinib compared to a control group of human patients treatedwith placebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the method is a method of treating adult patientssuffering from moderately to severely active Crohn's disease that isstatistically significantly superior to placebo, comprising orallyadministering once daily to each patient an induction dose of 45 mg ofupadacitinib once daily for 12 weeks, wherein the method results in astatistically significantly greater percentage of patients achievingclinical remission per Crohn's Disease Activity Index (CDAI) at 12 weeksafter the administration of the initial induction dose of 45 mg ofupadacitinib compared to a control group of human patients treated withplacebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the method further comprises orally administering tothe patient, after the last induction dose of 45 mg of upadacitinib, amaintenance dose of 15 mg of upadacitinib once daily, wherein astatistically significantly greater percentage of patients achieveclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 15 mg ofupadacitinib compared to a control group of human patients treated withplacebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the adult patient is suffering from refractory orseverely active Crohn's disease and the method further comprises orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 30mg of upadacitinib of upadacitinib compared to a control group of humanpatients treated with placebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of the study design for theclinical study described in Example 8.

FIG. 2 is a schematic representation of the 36-week extension phase forthe clinical study described in Example 8. Patients who did notadequately respond during the double-blind portion of the extensionphase were eligible to receive open-label therapy.

FIGS. 3A-3I are graphs depicting the relationship between upadacitinibplasma concentration and clinical response (Week 16; FIG. 3A), (NRI)clinical remission (Week 16; FIG. 3B), modified clinical remission (Week16; FIG. 3C); decrease in CDAI≥70 (Week 16; FIG. 3D); decrease inCDAI≥100 (Week 16; FIG. 3E); CDAI<150 (Week 16; FIG. 3F); endoscopicresponse (Week 12 or Week 16; FIG. 3G); endoscopic improvement (Week 16;FIG. 3H); and endoscopic remission (Week 12 or Week 16; FIG. 3I) asdetermined in the Example 8 clinical study. Arrows indicate the medianexposure (in mg) for each immediate release dose. The maximum andminimum plasma concentrations for each exposure bin are indicated inbrackets.

FIGS. 4A-4F are graphs depicting the model-predicted efficacy (NRI) fordifferent upadacitinib doses for immediate-release (IR) BID formulationsor modified-release (MR) QD formulations (simulating for 200patients/arm) at Weeks 12 or 16. The predicted results are based on theexposure-response relationships as determined in the Example 8 study.

FIGS. 5A-5H are graphs depicting the relationship between upadacitinibplasma concentration and the change from baseline for select measuredlaboratory parameters at week 16 (LOCF) of the Example 8 clinical study.The maximum and minimum plasma concentrations for each data point areindicated in brackets.

FIGS. 6A and 6B are graphs depicting the percent of subjects whoachieved clinical response or clinical remission at week 12 of theExample 8 study. FIG. 6A shows results for subjects who were not onsteroids at baseline, and FIG. 6B shows results for subjects who were onsteroids at baseline, and who underwent mandatory taper of steroid dose,starting at week 2 of the Example 8 clinical study.

FIG. 7 shows the upadacitinib mean plasma concentration versus timefollowing administration of 6 mg twice daily immediate release capsules(Regimen K) or a 15 mg once-daily modified release tablet (Regimen L)for seven days under fasting conditions.

FIG. 8 shows the upadacitinib mean plasma concentration versus timefollowing administration of 12 mg twice daily immediate release capsules(Regimen M) or a 30 mg once-daily modified release tablet (Regimen N)for seven days under fasting conditions.

FIG. 9 shows the clinical remission and endoscopic response in arefractory patient population administered upadacitinib or placebo inthe Example 8 Crohn's disease clinical study.

FIGS. 10A-10E are graphs depicting the percentage of subjects whoachieved modified clinical remission at week 2 (FIG. 10A), week 4 (FIG.10B), week 8 (FIG. 10C), week 12 (FIG. 10D) and week 16 (FIG. 10E) ofthe Example 8 study.

FIGS. 11A-11E are graphs depicting the percentage of subjects whoachieved enhanced clinical response at week 2 (FIG. 11A), week 4 (FIG.11B), week 8 (FIG. 11C), week 12 (FIG. 11D) and week 16 (FIG. 11E) ofthe Example 8 study.

FIG. 12 shows the mean change in hs-CRP (percentage over baseline)versus time (weeks) following administration of placebo (PBO),upadacitinib at 3, 6, 12, 24 mg twice daily (BID) and 24 mg once daily(QD) for 16 weeks. Modified clinical remission was analyzed in patientswith SF≥4, AP≥2.0 at baseline.

FIG. 13 is a schematic representation of the study design for theulcerative colitis clinical study described in Example 12.

FIG. 14 schematically illustrates one method of preparing the AmorphousFreebase.

FIG. 15 schematically illustrates one method of preparing the FreebaseHydrate Form C.

FIG. 16 schematically illustrates one method of preparing the TartrateHydrate.

FIGS. 17A and 17B are powder X-ray diffraction patterns corresponding tothe Amorphous Freebase (via precipitation) and the Amorphous Freebase(via dehydration), respectively.

FIG. 18 is a powder X-ray diffraction pattern corresponding to theFreebase Solvate Form A (Isopropyl Acetate/Water Solvate).

FIG. 19 is a powder X-ray diffraction pattern corresponding to theFreebase Hydrate Form B.

FIG. 20 is a powder X-ray diffraction pattern corresponding to theFreebase Hydrate Form C.

FIG. 21 is a powder X-ray diffraction pattern corresponding to theTartrate Hydrate. The experimental PXRD pattern is shown at the bottomof FIG. 21 and the calculated PXRD pattern is shown at the top of FIG.21.

FIG. 22 is a powder X-ray diffraction pattern corresponding to theFreebase Anhydrate Form D.

FIGS. 23A-23F are graphs depicting the exposure-response model-predictedefficacy for clinical and endoscopic endpoints for extended-releaseformulation QD regimens. FIG. 23A is the percentage of subjectspredicted to achieve clinical response at week 12; FIG. 23B is thepercentage of subjects predicted to achieve modified clinical remissionat week 12; FIG. 23C is the percentage of subjects expected to achieveCDAI remission at week 12; FIG. 23D is the percentage of subjectspredicted to achieve endoscopic response at week 12/16; FIG. 23E is thepercentage of patients predicted to achieve endoscopic improvement atweek 12/16; FIG. 23F is the percentage of patients predicted to achieveendoscopic remission at week 12/16.

FIG. 24 shows the clinical remission at week 8 in a patient populationadministered upadacitinib or placebo in the Example 19 ulcerativecolitis clinical study, based on achieving an Adapted Mayo score ≤2,with SFS≤1 and not greater than baseline, RBS of 0, and endoscopicsubscore ≤1.

FIG. 25 shows the clinical response rate for weeks 2 to 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving a decrease inPartial Adapted Mayo score ≥1 point and ≥30% from Baseline, PLUS adecrease in RBS≥1 or an absolute RBS≤1

FIG. 26A shows the clinical response rate at week 2 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving a decrease inPartial Adapted Mayo score ≥1 point and ≥30% from Baseline, PLUS adecrease in RBS≥1 or an absolute RBS≤1

FIG. 26B shows the clinical response rate at week 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving a decrease inPartial Adapted Mayo score ≥1 point and ≥30% from Baseline, PLUS adecrease in RBS≥1 or an absolute RBS≤1

FIG. 27A shows the endoscopic improvement rate at week 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving an endoscopicscore ≤1.

FIG. 27B shows the endoscopic remission rate at week 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving an endoscopicscore of 0.

FIG. 28A shows the histologic improvement rate at week 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving any decrease frombaseline in the Geboes score.

FIG. 28B shows the Histologic Endoscopic Mucosal Improvement (HEMI) rateat week 8 in a patient population administered upadacitinib or placeboin the Example 19 ulcerative colitis clinical study, based on achievingan Endoscopic subscore of 0 or 1 and a Geboes score ≤3.1.

FIG. 28C shows the Mucosal Healing rate at week 8 in a patientpopulation administered upadacitinib or placebo in the Example 19ulcerative colitis clinical study, based on achieving an Endoscopicscore of 0 and a Geboes score less than 2.

FIG. 29 is a table summarizing the study endpoints at week 52 andpercentage of subjects achieving each endpoint in the Example 20 UCmaintenance study.

FIG. 30 shows the proportion of subjects with clinical response perPartial Adapted Mayo Score over time in the Example 20 UC maintenancestudy.

FIG. 31 shows the proportion of subjects with clinical remission perPartial Mayo Score over time in the Example 20 UC maintenance study.

FIG. 32 is a Forest plot for the subgroup analysis of clinical remissionper Adapted Mayo score at week 52 for the 15 mg dose of upadacitinib vs.placebo in the Example 20 study.

FIG. 33 is a Forest plot for the subgroup analysis of clinical remissionper Adapted Mayo score at week 52 for the 30 mg dose of upadacitinib vs.placebo in the Example 20 study.

FIG. 34 shows the results for the primary endpoint of clinical remissionat week 52 per Adapted Mayo Score for both doses of upadacitinib vs.placebo in the Example 20 study.

FIGS. 35A-35C show the percentage of subjects achieving the endpoints ofsustained response (FIG. 35A), sustained remission (FIG. 35B), andcorticosteroid free remission (FIG. 35C) for both doses of upadacitinibvs. placebo in the Example 20 study.

FIGS. 36A-36C show the percentage of subjects achieving the endpoints ofendoscopic improvement (FIG. 36A), sustained endoscopic improvement(FIG. 36B), and endoscopic remission (FIG. 36C) for both doses ofupadacitinib vs. placebo in the Example 20 study.

FIGS. 37A-37B show the percentage of subjects achieving the endpoints ofHistologic-Endoscopic Improvement (HEMI) (FIG. 37A) and MucosalHealing-Endoscopic and Histologic Assessment (FIG. 37B) in the Example20 study.

FIG. 38A-38B show the percentage of subjects achieving the endpoints ofsymptom improvement (no abdominal pain (FIG. 38A) and no bowel urgency(FIG. 38B)) in the Example 20 study.

FIGS. 39A-39B show the change from induction baseline in quality of lifemeasures using the IBDQ vhange scale (FIG. 39A) and FACIT-F change scale(FIG. 39B) in the Example 20 study.

FIGS. 40A-40E are a series of graphs demonstrating the observedexposure-response relationship between upadacitinib efficacy at week 52in UC and average plasma concentration (C_(avg)) quartiles in theoverall study population across various endpoints in the Example 20study.

FIGS. 41A-41E are a series of graphs demonstrating the observedexposure-response relationship between upadacitinib efficacy at week 52in UC and average plasma concentration (C_(avg)) quartiles stratified byclinical remission status at end of induction across various endpointsin the Example 20 study.

FIG. 42 is a schematic representation of a study design for Crohn'sdisease phase 3 clinical studies.

FIG. 43 is a more detailed schematic representation of the study designof FIG. 42.

FIG. 44 is a table providing endpoints, definitions, and rankings forthe clinical study described in Example 21.

FIG. 45 is a schematic representation of the design of Parts 1 and 2 forthe Crohn's disease clinical study described in Example 21.

FIG. 46 is a schematic representation of the design for Part 3 of theCrohn's disease clinical study described in Example 21.

FIG. 47 is a graph showing the proportions of subjects achievingclinical remission and endoscopic response at week 12 for upadicitinib45 mg QD versus placebo in the Example 21 study.

FIG. 48 is a graph showing the clinical remission rates per CDAI overtime for subjects on upadicitinib 45 mg QD or placebo in the Example 21study.

FIG. 49 is a graph showing the clinical remission rates per PRO overtime for subjects on upadicitinib 45 mg QD or placebo in the Example 21study.

FIG. 50 is a graph showing the proportion of subjects achievingendoscopic response and endoscopic remission at week 12 for upadicitinib45 mg QD versus placebo in the Example 21 study.

FIG. 51 is a graph showing the proportions of subjects achievingsteroid-free clinical remission at week 12 for upadicitinib 45 mg QDversus placebo in the Example 21 study.

FIG. 52 is a schematic representation of the design for Substudy 1 ofthe Crohn's disease clinical study described in Example 22.

FIG. 53 is a schematic representation of the design for Substudy 2 ofthe Crohn's disease clinical study described in Example 22.

FIG. 54 is a table providing a tapering schedule for prednisone,prednisolone, and budesonide corticosteroids for the Example 22 study.

FIG. 55 is a table providing a tapering schedule for methylprednisoloneand hydrocortisone corticosteroid for the Example 22 study.

FIGS. 56A-56C are graphs showing the proportion of subjects achievingclinical remission per PRO, clinical remission per CDAI, and endoscopicresponse, respectively, for placebo, upadacitinib 15 mg QD, andupadacitinib 30 mg QD in the Example 22 study.

FIG. 57A is a graph showing the proportion of subjects achievingclinical remission per PRO for placebo, upadacitinib 15 mg QD, andupadacitinib 30 mg QD in non-biologic-inadequate responders (Non-Bio-IR)and biologic-inadequate responders (Bio-IR) in the Example 22 study.

FIG. 57B is a graph showing the proportion of subjects achievingclinical remission per CDAI for placebo, upadacitinib 15 mg QD, andupadacitinib 30 mg QD in non-biologic-inadequate responders (Non-Bio-IR)and biologic-inadequate responders (Bio-IR) in the Example 22 study.FIG. 57C is a graph showing the proportion of subjects achievingendoscopic response for placebo, upadacitinib 15 mg QD, and upadacitinib30 mg QD in non-biologic-inadequate responders (Non-Bio-IR) andbiologic-inadequate responders (Bio-IR) in the Example 22 study.

FIG. 58 is a graph showing the rates of clinical remission per PRO ateach visit, as well as corresponding 95% confidence intervals (CIs), forplacebo, upadacitinib 15 mg, and upadacitinib 30 mg in the Example 22study.

FIG. 59 is a graph showing the rates of clinical remission per CDAI ateach visit, as well as corresponding 95% confidence intervals (CIs), forplacebo, upadacitinib 15 mg, and upadacitinib 30 mg in the Example 22study.

FIG. 60A is a graph showing the proportion of subjects achievingsteroid-free clinical remission per PRO among subjects on steroids atbaseline for placebo, upadacitinib 15 mg, and upadacitinib 30 mg in theExample 22 study.

FIG. 60B is a graph showing the proportion of subjects achievingsteroid-free clinical remission per CDAI among subjects on steroids atbaseline for placebo, upadacitinib 15 mg, and upadacitinib 30 mg in theExample 22 study.

FIG. 60C is a graph showing the proportion of subjects achievingsteroid-free clinical remission per PRO among all subjects for placebo,upadacitinib 15 mg, and upadacitinib 30 mg in the Example 22 study.

FIG. 60D is a graph showing the proportion of subjects achievingsteroid-free clinical remission per CDAI among all subjects for placebo,upadacitinib 15 mg, and upadacitinib 30 mg in the Example 22 study.

FIG. 61A is a graph showing the proportion of subjects achievingendoscopic response at Week 52 with for placebo, upadacitinib 15 mg, andupadacitinib 30 mg in the Example 22 study.

FIG. 61B is a graph showing the proportion of subjects achievingendoscopic remission at Week 52 with for placebo, upadacitinib 15 mg,and upadacitinib 30 mg in the Example 22 study.

FIG. 62A is a graph showing the proportion of subjects achievingmaintenance of clinical remission per PROs and CDAI for placebo,upadacitinib 15 mg, and upadacitinib 30 mg in the Example 22 study.

FIG. 62B is a graph showing the proportion of subjects achieving deepremission per PROs and CDAI among all subjects for placebo, upadacitinib15 mg, and upadacitinib 30 mg in the Example 22 study.

DETAILED DESCRIPTION OF THE DISCLOSURE

This written description uses examples to disclose the invention andalso to enable any person skilled in the art to practice the invention,including making and using any of the disclosed compositions, andperforming any of the disclosed methods or processes. The patentablescope of the invention is defined by the claims, and may include otherexamples that occur to those skilled in the art. Such other examples areintended to be within the scope of the claims if they have elements thatdo not differ from the literal language of the claims, or if theyinclude equivalent elements.

I. Definitions

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

The term “abdominal pain” referes to pain originating from organs withinthe abdominal cavity including the stomach, small intestine, and colon.Abdominal pain can range in intensity from a mild to severe acute pain,and may be acute or chronic. Abdominal pain symptoms were collected bythe patient and recorded daily in an electronic diary (e-diary) using anelectronic handheld device, and scored as 0 (no pain), 1 (mild pain), 2(moderate pain), or 3 (severe pain).

The term “Adapted Mayo” or “Adapted Mayo score” when used in connectionwith ulcerative colitis refers to the Mayo Scoring System for Assessmentof Ulcerative Colitis Activity, excluding the Physician's GlobalAssessment subscore.

The term “adult” refers to a person 16 years of age or older.

The abbreviation “AE” refers to adverse event.

The term “alkyl” refers to straight chained or branched hydrocarbonswhich are completely saturated. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention,examples of alkyls include methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl, and isomers thereof.

The term “alkenyl” refers to a hydrocarbon moiety containing two toeight carbons, including straight chained or branched hydrocarbons whichcontain one or more double bonds. Non-limiting examples of alkenyls areethenyl, propenyl, and butenyl.

The term “amorphous” as applied to a compound refers to a state in whichthe material lacks long range order at the molecular level and,depending upon temperature, may exhibit the physical properties of asolid or a liquid. Typically, such materials do not give distinctiveX-ray diffraction patterns and, while exhibiting the properties of asolid, are more formally described as a liquid. Upon heating, a changefrom solid to liquid properties occurs which is characterized by achange of state, typically second order (“glass transition”).

The term “anhydrate” as applied to a compound refers to a solid statewherein the compound contains no structural water within the crystallattice.

The abbreviation “AP” refers to abdominal pain score. Unless otherwiseindicated, the AP measurement discussed herein is an unweighted averageof daily AP scores for seven days. The AP measurements are calculated byaveraging the daily AP score used in calculating the CDAI (discussedbelow), without the weighting factor applied.

The term “aryl” refers to a mono-, bi-, or tricyclic aromatichydrocarbon radical. Examples include phenyl, naphthyl, biphenyl, and1,2,3,4-tetrahydronaphthyl.

As used herein, the term “AUC₂₄” refers to the area under the plasmaconcentration time curve from time zero to twenty-four hours afteradministration of the referent drug following a single dose.

The term “baseline” refers to the day of first dosing with the JAK1inhibitor, and is also referred to herein as “Day 1” or “Week 0”.

The abbreviation “BID” means twice a day.

The abbreviation “BL” means baseline.

As used herein, the term “bowel urgency” refers to a sudden, nearlyuncontrollable need to defecate. Bowel urgency data were collected bythe patient and recorded daily in an electronic diary (e-diary) using anelectronic handheld device as a yes/no response with regard to symptompresence.

As used herein, the term “C₁₂” is the plasma concentration of thereferent drug observed 12 hours after administration of a single dose,or the indicated number of doses, of the referent drug.

As used herein, the term “C₂₄” is the plasma concentration of thereferent drug observed 24 hours after administration of a single dose,or the indicated number of doses, of the referent drug.

The term “C_(ave)” refers to the average plasma concentration of a drugduring a dosage interval at steady-state (multiple-dosing).

The abbreviation “Cbz” refers to carboxybenzyl.

The abbreviation “CDI” refers to carbonyldiimidazole.

The abbreviation “CI” means confidence interval.

The abbreviation “CDAI” means Crohn's Disease Activity Index.

The term “clinical remission” when used in connection with Crohn'sdisease means average daily liquid/very soft stool frequency ≤2.8 andnot greater than baseline and average daily abdominal pain ≤1.0 and notgreater than baseline. As used in connection with clinical remission ofCrohn's disease, the phrase “not greater than baseline” means theaverage daily SF or average daily AP score is not higher than theaverage daily SF score or average daily AP score, respectively, atbaseline (i.e., prior to treatment).

The term “clinical remission” when used in connection with ulcerativecolitis means a stool frequency (SF) subscore ≤1, a rectal bleedingsubscore (RBS) of 0, and an endoscopic subscore of ≤0. The SF subscore,rectal bleeding subscore, and endoscopic subscore refer to the subscoresused in the Mayo Scoring System for Assessment of Ulcerative ColitisActivity. This is also referred to as “clinical remission per AdaptedMayo Score”.

The term “clinical response” when used in connection with Crohn'sdisease is defined as an average daily liquid/very soft SF scorereduction of at least 30% from BL (i.e., ≥30% decrease from BL) and anaverage daily AP not greater than BL and/or “clinical response” isdefined as an average daily AP score reduction of at least 30% from BL(i.e., ≥30% decrease from BL), and an average daily liquid/very soft SFscore not greater than at BL (i.e., prior to treatment).

The term “clinical response” when used in connection with ulcerativecolitis is defined as a decrease from baseline in the Adapted Mayo score≥2 points and ≥30% from baseline accompanied by a decrease in RBS≥1 oran absolute RBS≤1.

The term “enhanced clinical response” when used in connection withCrohn's disease is defined as ≥60% decrease in average daily SF and/or≥35% decrease in average daily AP and both not greater than baseline,and/or clinical remission.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The term “C_(max)” refers to the plasma concentration of the referentdrug at T_(max), expressed herein as ng/mL, produced by the oralingestion of a single dose, or indicated number of doses, of the dosageform or pharmaceutical composition, such as the dosage forms andcompositions of the present disclosure. Unless specifically indicated,C_(max) refers to the overall maximum observed concentration.

The term “C_(max)” refers to the minimum concentration of drug in bloodplasma.

The term “corticosteroid-free” means a patient who was takingcorticosteroids at the time of the first induction dose of upadacitiniband has completely discontinued use of corticosteroids.

The term “C_(p)” refers to plasma drug concentration at any time t.

The term “crystalline” as applied to a compound refers to a solid phasein which the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (“meltingpoint”).

The term “crystallization” as used throughout this application can referto crystallization and/or recrystallization depending upon theapplicable circumstances relating to the preparation of the compound.

The abbreviation “% CV” refers to the coefficient of variation,expressed as a percent. % CV is calculated according to the followingequation: % CV=(SD/x)*100, wherein x is the mean value and SD is thestandard deviation.

A “disorder”, as used herein, is any condition that would benefit fromtreatment with a JAK1 inhibitor described herein. This includes chronicand acute disorders or diseases including those pathological conditionsthat predispose a mammal to the disorder in questions.

The term “endoscopic healing” means an SES-CD ulcerated surface subscoreof 0 in subjects with SES-CD ulcerated surface subscore ≥1 at baseline.

The term “endoscopic improvement” (also known as “endoscopic response by50%”) when used in connection with Crohn's disease means decrease inSES-CD>50% from baseline (or for subjects with an SES-CD of 4 atbaseline of the induction study, at least a 2 point reduction frombaseline).

The term “endoscopic improvement” when used in connection withulcerative colitis means an endoscopic subscore ≤1 at week 8 during theinduction phase and an endoscopic subscore of 0 at week 8 during themaintenance phase. The endoscopic subscore refers to the subscore usedin the Mayo Scoring System for Assessment of Ulcerative ColitisActivity.

The term “endoscopic remission”, when used in connection with Crohn'sdisease, unless otherwise indicated, means an SES-CD of ≤4 (≤2 forpatients with isolated ileal CD) and at least a two point reduction inSES-CD versus BL and no subscore ≥1 in any individual variable used tocalculate the SES-CD.

The term “endoscopic remission (by IOIBD (International Organization forthe Study of Inflammatory Bowel Diseases) definition), when used inconnection with Crohn's disease, means SDS≤2.

The term “endoscopic remission” when used in connection with ulcerativecolitis means an endoscopic subscore of 0. The endoscopic subscore referto the endoscopic subscore used in the Mayo Scoring System forAssessment of Ulcerative Colitis Activity.

The term “endoscopic response” when used in connection with Crohn'sdisease means at least a 50% reduction in SES-CD score from BL.

The abbreviation “EtOAc” refers to ethyl acetate.

The abbreviation “EtOH” refers to ethanol.

The term “Geboes score” means a histological score based on measurementof fecal calprotein and high-sensitivity C-reactive protein.

The term “histologic improvement” when used in connection withulcerative colitis means a decrease from baseline in Geboes score.

The abbreviation “HDL” refers to high density lipoprotein.

The abbreviation “Hgb” refers to hemoglobin.

The abbreviation “HOAc” refers to acetic acid.

The abbreviation “HPMC” refers to hydroxypropyl methylcellulose.

As used herein, the term “inducing” or “induced”, when used inconnection with a particular therapeutic effect, means the therapeuticeffect has been achieved. Typically, the therapeutic effect is inducedin a patient previously suffering from a disease condition, such as in apatient having moderately to severely active Crohn's disease ormoderately to severely active ulcerative colitis. For instance, in oneembodiment, inducing a particular therapeutic effect, when used inconnection with Crohn's disease, means the patient is brought from astate where the patient has 1) an average daily liquid/very soft stoolfrequency score ≥2.5 or average daily abdominal pain score ≥2, 2)CDAI≥220 and ≤450 or 3) Simplified Endoscopic Score for Crohn's disease(SES-CD)≥6 (or ≥4 for subjects with disease limited to the ileum) andbringing the patient to a state where the patient achieve the parametersfor the specified therapeutic effect (e.g., endoscopic remission,clinical remission, endoscopic response, clinical response).

The abbreviation “IPAc” refers to isopropyl acetate.

The abbreviation “IR” means immediate release, unless otherwiseindicated.

As used herein, the term “JAK1 inhibitor” or “upadacitinib” refers tothe compound (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

The abbreviation “LDL” refers to low density lipoprotein.

The abbreviation “LOCF” means last observation carried forward method.

The abbreviation “Mayo” means the Mayo Scoring System for Assessment ofUlcerative Colitis Activity.

The term “moderately to severely active Crohn's disease”, unlessotherwise indicated, is defined as average daily very soft orlliquid/soft stool frequency ≥4 and/or average daily abdominal painscore ≥2.0 and evidence of mucosal inflammation, defined as SimplifiedEndoscopic Score ofor CD (SES-CD)≥6 (≥4 for subjects with isolated ilealdisease), excluding the presence of narrowing component.

The term “moderately to severely active ulcerative colitis”, unlessotherwise indicated, is defined as having an Adapted Mayo score of 5 to9, with an endoscopy subscore of 2 or 3.

The term “modified clinical remission” when used in connection withCrohn's disease is defined as an average daily liquid/very soft SF scoreof ≤2.8 and not greater than BL and an average daily AP score of ≤1.0and not greater than BL. As used in connection with clinical remission,the phrase “not greater than baseline” means that average dailyliquid/very soft SF score or average daily AP score is not higher thanthe average daily liquid/very soft SF score or average daily AP score,respectively, at baseline (i.e., prior to treatment).

The abbreviation “MR” means modified release.

The abbreviation “MTX” refers to methotrexate.

The term “Mucosal Healing” when used in connection with ulcerativecolitis means an endoscopic subscore of 0 and a Geboes score of ≤2.0.

The term “patient” or “subject”, used interchangeably herein, refers toa human patient or subject.

The term “NK cells” refers to natural killer cells.

The abbreviation “NRI” means non-responder imputation method.

The abbreviation “PBO” means placebo.

The abbreviation “Pd/C” refers to palladium on carbon.

The abbreviation “Pd(OH₂)/C” refers to palladium hydroxide on carbon.

The term “pharmaceutically acceptable” (such as in the recitation of a“pharmaceutically acceptable salt” or a “pharmaceutically acceptablediluent”) refers to a material that is compatible with administration toa human subject, e.g., the material does not cause an undesirablebiological effect. Examples of pharmaceutically acceptable salts aredescribed in “Handbook of Pharmaceutical Salts: Properties, Selection,and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).Examples of pharmaceutically acceptable excipients are described in the“Handbook of Pharmaceutical Excipients,” Rowe et al., Ed.(Pharmaceutical Press, 7th Ed., 2012).

The abbreviation “pTsOH” refers to p-toluene sulfonic acid.

The abbreviation “PVA” refers to polyvinyl acetate.

The abbreviation “PXRD” means powder X-ray diffraction.

The abbreviation “QD” means once daily.

The abbreviation “RBC” means red blood cells.

The abbreviation “RBS” means rectal bleeding subscore. The rectalbleeding subscore refers to the subscore used in the Mayo Scoring Systemfor Assessment of Ulcerative Colitis Activity.

The term “refractory patient” means a patient with moderately toseverely active Crohn's disease, who has had Crohn's disease for morethan ten years and who has failed several treatments, including biologictreatments.

The term “remission” when used in connection with Crohn's disease isdefined as both endoscopic remission and clinical remission.

The term “response” when used in connection with Crohn's disease isdefined as both endoscopic response and clinical response.

The abbreviation “SC” means subcutaneous.

The abbreviation “(S)-Segphos Ru(OAc)₂” refers todiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II).

The term “SES-CD” refers to the Simplified Endoscopic Score for Crohn'sdisease, which is calculated using the parameters listed in Table 2below.

The abbreviation “SF” refers to stool frequency. Unless otherwiseindicated, the SF measurement discussed herein when used in connectionwith Crohn's disease is an unweighted average of daily liquid/very softSF scores for seven days. The SF measurements are calculated byaveraging the daily liquid/very soft SF scores used in calculating theCDAI (discussed below), without the weighting factor applied. Unlessotherwise indicated, the SF measurement discussed herein when used inconnection with ulcerative colitis refers to the stool frequencysubscore used in the Mayo Scoring System for Assessment of UlcerativeColitis Activity.

The term “therapeutically effective amount” is used to refer to anamount of an active agent that relieves or ameliorates one or more ofthe symptoms of the disorder being treated. In another aspect, thetherapeutically effective amount refers to a target serum concentrationthat has been shown to be effective in, for example, slowing diseaseprogression. Efficacy can be measured in conventional ways, depending onthe condition to be treated.

The abbreviation “6-TGN” refers to 6-tioguanine (thioguanine)nucleotides.

The abbreviation “THF” refers to tetrahydrofuran.

As used herein, the term “T_(max)” refers to the time to peak plasmaconcentration of the referent drug after oral ingestion of a singledose, or indicated number of doses, of the referent drug.

The terms “treating”, “treatment”, and “therapy” and the like, as usedherein, are meant to include therapeutic as well as prophylactic, orsuppressive measures for a disease or disorder leading to any clinicaldesirable or beneficial effect, including but not limited to alleviationor relief of one or more symptoms, regression, slowing or cessation ofprogression of the disease or disorder. Thus, for example, the termtreatment includes the administration of an agent prior to or followingthe onset of a symptom of a disease or disorder thereby preventing orremoving one or more signs of the disease or disorder. As anotherexample, the term includes the administration of an agent after clinicalmanifestation of the disease to combat the symptoms of the disease.Further, administration of an agent after onset and after clinicalsymptoms have developed where administration affects clinical parametersof the disease or disorder, such as the degree of tissue injury or theamount or extent of metastasis, whether or not the treatment leads toamelioration of the disease, comprises “treatment” or “therapy” as usedherein. Moreover, as long as the compositions of the disclosure eitheralone or in combination with another therapeutic agent alleviate orameliorate at least one symptom of a disorder being treated as comparedto that symptom in the absence of use of the JAK1 inhibitor composition,the result should be considered an effective treatment of the underlyingdisorder regardless of whether all the symptoms of the disorder arealleviated or not.

The abbreviation “TNF” means tumor necrosis factor.

As used herein, the term “t_(1/2)” refers to the terminal half-life ofthe referent drug after oral ingestion of a single dose, or indicatednumber of doses, of the referent drug.

The abbreviation “UC” refers to ulcerative colitis.

The abbreviation “w/w” refers to weight/weight.

II. JAK1-Associated Disorders and JAK1 Inhibitors

In one aspect, the present disclosure provides methods for treatingand/or inducing clinical remission, endoscopic improvement, and/orendoscopic remission of Crohn's disease. In another aspect, the presentdisclosure provides methods for treating ulcerative colitis and/or forinducing a clinical remission of ulcerative colitis. In one aspect, themethods comprise administering a JAK1 inhibitor to the patient.

Targeting the JAK (Janus activated kinase) signaling pathway forautoimmune diseases, such as rheumatoid arthritis (RA) and CD, iswell-supported by the involvement of various pro-inflammatory cytokinesthat signal via JAK pathways in the pathogenesis of these immune-relateddisorders. The activation of the JAK signaling initiates expression ofsurvival factors, cytokines, chemokines, and other molecules thatfacilitate leukocyte cellular trafficking and cell proliferation, whichcontribute to inflammatory and autoimmune disorders.

Although the pathogenesis of CD is not completely understood, theimbalance between anti-inflammatory and pro-inflammatory cytokines inthe mucosal immune system is thought to play an important role in CD.Cells from the innate mucosal immune system, i.e. TH1 or TH17, areover-activated and secrete various pro-inflammatory cytokines such asinterferon (INF)-g, TNFα, interleukin IL-6, IL 1b, IL-12, IL23. Thesecytokines signal via JAK pathways.

The JAK comprises four family members: JAK1, 2, 3, and Tyrosine kinase 2(Tyk2). These cytoplasmic tyrosine kinases transduce cytokine-mediatedsignals, and are associated with membrane cytokine receptors such ascommon gamma-chain (CGC) receptors and the glycoprotein 130 (gp130)trans-membrane proteins.

JAK3 and JAK1 are components of the CGC cytokine receptor complexes andblockade of either inhibits signaling by the inflammatory cytokinesIL-2, -4, -7, -9, -15 and -21. Cytokines such as IL-6 bind to gp130 andtransduce its signal predominantly via JAK1. Targeting the IL-6 receptor(IL-6R) is a promising approach given the fact that expression of IL-6and soluble IL-6 receptors is elevated in patients with active CD.Further, a proof of concept study in patients with active CD withtocilizumab, a humanized monoclonal antibody against IL-6R, showed anencouraging clinical response. Thus, inhibition of JAK1 is expected toattenuate the signaling of IL-6 and other pro-inflammatory cytokines(i.e. IFN-g), that are involved in development of CD.

Thus, in one aspect, the present disclosure provides a compound usefulin the treatment of Crohn's Disease and ulcerative colitis. In oneaspect, the JAK1 inhibitor used in the methods of the present disclosureis the compound (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(C₁₇H₁₉F₃N₆O), or a pharmaceutically acceptable salt or solid state formthereof. The compound(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamideis also referred to herein as “upadacitinib”, and has the structureshown below:

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, mono-malic acid, monooxalic acid, tartaric acid such as mono tartaric acid (e.g., (+) or(−)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art

III. Methods of Treatment of Crohn's Disease

In one aspect, the present disclosure is directed to methods for thetreatment of Crohn's disease. In one aspect, the present disclosureprovides methods for treating Crohn's disease, in particular methodscomprising administering a JAK1 inhibitor to a patient in certainamounts and/or at certain intervals. In one aspect, the JAK1 inhibitoris upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof.

In one aspect, the present disclosure provides a JAK1 inhibitor for usein the treatment of Crohn's disease, by administration in certainamounts and/or at certain intervals as described herein. In one aspect,the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable saltor solid state form thereof.

In one aspect, the present disclosure provides for the use of a JAK1inhibitor for the preparation of a medicament for the treatment ofCrohn's disease, by administration in certain amounts and/or at certainintervals as described herein. In one aspect, the JAK1 inhibitor isupadacitinib or a pharmaceutically acceptable salt or solid state formthereof.

In one aspect, the present disclosure is directed to methods forinducing clinical remission and/or endoscopic remission of Crohn'sdisease. In one aspect, the present disclosure provides methods forinducing clinical remission and/or endoscopic remission of Crohn'sdisease, in particular methods comprising administering a JAK1 inhibitorto a patient in certain amounts and/or at certain intervals. In oneaspect, the JAK1 inhibitor is upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof.

In one aspect, the present disclosure provides a JAK1 inhibitor for usein inducing clinical remission and/or endoscopic remission of Crohn'sdisease by administration in certain amounts and/or at certain intervalsas described herein. In one aspect, the JAK1 inhibitor is upadacitinibor a pharmaceutically acceptable salt or solid state form thereof.

In one aspect, the present disclosure provides for the use of a JAK1inhibitor for the preparation of a medicament for inducing clinicalremission and/or endoscopic remission of Crohn's Disease byadministration in certain amounts and/or at certain intervals asdescribed herein. In one aspect, the JAK1 inhibitor is upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

In one aspect, the present disclosure is directed to methods forinducing clinical remission and/or endoscopic improvement of Crohn'sdisease, in particular, methods comprising administering a JAK1inhibitor to a patient in certain amounts and/or at certain intervals.In one aspect, the JAK1 inhibitor is upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof.

In one aspect, the present disclosure provides a JAK1 inhibitor for usein inducing clinical remission and/or endoscopic improvement of Crohn'sdisease by administration in certain amounts and/or at certain intervalsas described herein. In one aspect, the JAK1 inhibitor is upadacitinibor a pharmaceutically acceptable salt or solid state form thereof.

In one aspect, the present disclosure provides for the use of a JAK1inhibitor for the preparation of a medicament for inducing clinicalremission and/or endoscopic improvement of Crohn's disease, byadministration in certain amounts and/or at certain intervals asdescribed herein. In one aspect, the JAK1 inhibitor is upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

In one particular aspect, the disease is moderately to severely activeCrohn's disease. In one aspect, in the context of the presentdisclosure, a patient is naïve to, or was previously treated withimmunosuppressants (e.g., methotrexate), aminosalicylates,corticosteroids, and/or a biologic agent (e.g., vedolizumab,ustekinumab, natalizumab, etc.). In one aspect, the patient is naïve to,or was previously treated with an anti-TNF therapy (e.g., infliximab,adalimumab, certolizumab pegol, golimumab, etc.). In one aspect, in thecontext of a method of the present disclosure a patient was previouslytreated with one, two, three or more TNF antagonist(s) (also referred toherein as anti-TNF agents). In one embodiment, the patient is a patientwho had an inadequate response with, lost response, or was intolerant toa TNF antagonist. In one aspect, in the context of a method of thepresent disclosure a patient was previously treated with one, two, threeor more biologic(s). In one embodiment, the patient is a patient who hadan inadequate response with, lost response, or was intolerant to abiologic agent. In one embodiment, the patient is a patient who had aninadequate response with, lost response, or was intolerant to a TNFantagonist, aminosalicylates, corticosteroids, immunosuppressants,and/or a biologic agent. In one embodiment, the patient is a refractorypatient who has moderately to severely active Crohn's disease. In oneembodiment, the patient is either naïve to or has stopped usingcorticosteroids prior to treatment with the JAK1 inhibitor.

Biologic Agents for Crohn's Disease:

-   1) Demonstrated an inadequate response to, loss of response to,    recurrence of signs and symptoms or intolerance to any biologoic    therapy as defined below:    -   a. at least one 6-week induction regimen of infliximab (≥5 mg/kg        intravenous [IV] at 0, 2 and 6 weeks),    -   b. at least one 4-week induction regimen of adalimumab (one 160        mg subcutaneous (SC) dose at Week 0, followed by one 80 mg SC        dose at Week 2 [or one 80 mg SC dose at Week 0, followed by one        40 mg SC dose at at Week 2, in countries where this dosing        regimen is approved]),    -   c. at least one 4-week induction regimen of certolizumab pegol        (400 mg SC at Weeks 0, 2 and 4),    -   d. at least one 6-week induction regimen of vedolizumab (300 mg        W at 0, 2 and 6 weeks),    -   e. at least one 12-week induction regimen of natalizumab (300 mg        W every 4 weeks),    -   f. at least on 8-week induction regimen of ustekinumab [260 mg        (<55 kg) or 390 mg (56-85 kg) or 520 mg (>86 kg), followed by 90        mg SC at week 8] or-   2) Recurrence of symptoms during scheduled maintenance dosing    following prior clinical benefit (discontinuation despite clinical    benefit does not qualify), or-   3) History of intolerance to at least one biologic agent (including,    but not limited to infusion-related reaction, demyelination,    congestive heart failure (CHF), infection).

Disease severity for Crohn's disease may be measured using a variety ofindexes, including the Crohn's Disease Activity Index (CDAI), theSimplified Endoscopic Score for CD (SES-CD), average daily liquid/verysoft stool frequency (SF) (patient reported); and/or average dailyabdominal pain (AP) score (patient reported). Unless otherwiseindicated, the SF and AP scores discussed herein refer to theirrespective unweighted average of the daily scores that are used incalculation of the CDAI (discussed below). Measures for assessinghealth-related quality of life include the Inflammatory Bowel DiseaseQuestionnaire (IBDQ). The IBDQ is a well-known 32 item validatedquestionnaire that assesses a patient's inflammatory bowel diseasesymptoms, general well-being, and mood, and may be used as a tool toevaluate a patient's quality of life (Guyatt, et al., Gastroenterology,1989, 96:804-810). The IBDQ questionnaire is described in further detailbelow.

CDAI is a composite score used to quantify symptoms of patients withCrohn's disease. In one aspect, the index consists of eight factorsadded together after adjusting for a predefined weighting factor (seeTable 1 below). CDAI scores range from 0 to 600. Index values of 150 andbelow are associated with quiescent disease; values above 150 areassociated with active disease, and values above 450 are seen withextremely severe disease. In one aspect, a patient to be treated by amethod according to the present disclosure has a CDAI score of 220 to450 prior to treatment, which may be indicative of moderately toseverely active CD.

TABLE 1 Format for Calculation of the CDAI Weighting Clinical orlaboratory variable factor Number of liquid or very soft stools in theprevious 7 days x2 (sum of daily scores) AP (graded from 0 (mild) to 3(severe) on severity) each day x5 for 7 days (sum of daily score)General wellbeing, subjectively assessed from 0 (generally x7 well) to 4(terrible) each day for 7 days (sum of daily score) Number ofcomplications patient now has: (record 0 if none) x20 Arthritis/arthralgia Iritis/uveitis Erythema nodosum/pyodermagangrenosum/aphthous stomatitis Fissure, abscess and/or anal fistula(draining/non-draining) Other cutaneous fistula (draining/non-draining)Fever over 100° F. (37.8° C.) during past week Takinglomotil/imodium/loperamide or opiates for diarrhea x30  (0 = no, 1 =yes) Presence of an abdominal mass (0 as none, 2 as questionable, x10  5as defined) Hematocrit (Male: 47-hematocrit; Female: 42-hematocrit; ifx6 hematocrit > normal, enter 0 Percentage under standard weight x1

SES-CD is calculated using the following parameters listed in Table 2:

TABLE 2 Parameters for Calculating SES-CD Sigmoid Trans- and left verseRight Rectum colon Colon colon Ileum Total Size of Ulcers Enter: 0 ifnone 1 if aphthous ulcer (Ø 0.01 to 0.5 cm) 2 if large ulcers (Ø 0.05 to2 cm) 3 if very large ulcer (Ø > 2 cm) Ulcerated Surface Enter: 0 ifnone 1 if <10% 2 if 10%-30% 3 if >30% Affected Surface Enter: 0 ifunaffected segments 1 if <50% 2 if 50%-75% 3 if >75% Presence ofNarrowing Enter: 0 if none 1 if single, can be passed 2 if multiple, canbe passed 3 if cannot be passed Total=

In one aspect, the patient to be treated has moderately to severelyactive Crohn's disease. Moderately to severely active Crohn's disease ischaracterized by a SES-CD of greater than or equal to 6 (or a SES-CD ofgreater than or equal to 4 for patients with disease limited to theileum).

In one embodiment, the patient is a patient who had an inadequateresponse with, lost response, or was intolerant to a conventionaltherapy (e.g., aminosalicylates, corticosteroids, immunosuppressants),or to a biologic agent. In one embodiment, the patient is a patient whohad an inadequate response with, lost response, or was intolerant to aTNF antagonist. Examples of such anti-TNF agents include infliximab,adalimumab, and certolizumab pegol. Criteria for determining if apatient has had an inadequate response to or experienced intolerance toprevious treatment with an anti-TNF agent is defined as:

-   1) Signs and symptoms of persistently active disease despite a    history of at least one 4-week induction regimen of one of the    following agents:    -   Infliximab: 5 mg/kg IV, 2 doses at least 2 weeks apart,    -   Adalimumab: one 160 mg subcutaneous dose followed by one 80 mg        subcutaneous dose (or one 80 mg subcutaneous dose) followed by        one 40 mg dose at least 2 weeks apart,    -   Certolizumab pegol: 400 mg subcutaneous, two doses at least two        doses apart; or 2) Recurrence of symptoms during scheduled        maintenance dosing following prior clinical benefit        (discontinuation despite clinical benefit does not qualify); or-   2) Recurrence of symptoms during scheduled maintenance dosing    following prior clinical benefit (discontinuation despite clinical    benefit does not qualify); or-   3) History of intolerance of at least one TNF antagonist (including,    but not limited to infusion related reaction, demyelination,    congestive heart failure and infection).

In one aspect, the patient is one who has previously been treated with,or is currently being treated with aminosalicylates, immunosuppressants,corticosteroids, and/or a biologic agent.

In one aspect, CDAI or any of the evaluations described in the Examplesherein below is/are used to assess the efficacy of upadacitinib in thetreatment of Crohn's disease, for example moderately to severely activeCrohn's disease.

In one embodiment, in the context of the present disclosure, thetreatment of a patient, or the induction of clinical remission and/orendoscopic remission in a patient, or the induction of clinicalremission and/or endoscopic improvement in a patient comprises aninduction phase and a maintenance phase. In the induction phase, one ormore doses of the JAK1 inhibitor, for example referred to herein asinduction doses, are administered to the patient, for example, orally.In the maintenance phase, a first dose of the JAK1 inhibitor, forexample referred to herein as the maintenance dose, is administered tothe patient followed by at least one additional dose of the JAK1inhibitor, for example, also referred to herein as a maintenance dose.The maintenance doses are, for example, administered orally. The JAK1inhibitor may be, for example, upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. Examples of inductionphases and maintenance phases are described herein.

In one aspect, a certain therapeutic result is achieved by the patientduring or at the end of the induction phase, for example clinicalremission, endoscopic remission, or both clinical remission andendoscopic remission (referred to herein as “remission”). In one aspect,the patient achieves clinical remission during or by the end of theinduction phase. In one aspect, the patient achieves endoscopicremission during or by the end of the induction phase.

In another aspect, a certain therapeutic result is achieved by thepatient during or at the end of the induction phase, for exampleclinical remission, endoscopic improvement, or both clinical remissionand endoscopic improvement. In one aspect, the patient achieves clinicalremission during or by the end of the induction phase. In one aspect,the patient achieves endoscopic improvement during or by the end of theinduction phase

In one embodiment, the induction phase lasts for up to 16 weeks (e.g.,for up to 16 weeks following initiation of administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof). Thus, in one embodiment, the induction phase is 16 weeks. Inanother embodiment, the induction phase optionally lasts for less than16 weeks, for instance, for 2 weeks, for 4 weeks, for 5 weeks, for 6weeks, for 7 weeks, for 8 weeks, for 9 weeks, for 10 weeks, for 11weeks, for 12 weeks, for 13 weeks, for 14 weeks, or for 15 weeks. In oneaspect, the patient achieves an endoscopic remission within 12 weeks, orwithin 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneaspect, the patient achieves a clinical remission within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one aspect, the patientachieves an endoscopic improvement within 12 weeks, or within 16 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one aspect, the patientachieves a clinical remission within 12 weeks, or within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one embodiment, the patient achieves clinical remission within 2weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves clinical remission within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one embodiment, the patient achieves both 1) average dailyliquid/very soft SF score of ≤1.5 and not worse than BL, and 2) averagedaily AP score of ≤1.0 and not worse than baseline within 2 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. As used in connection withclinical remission, the phrase “not worse than baseline” means that theaverage daily liquid/very soft SF score or average daily AP score is nothigher than the average daily liquid/very soft SF score or average dailyAP score, respectively, at baseline (i.e., prior to treatment).

In one embodiment, the patient achieves both 1) average dailyliquid/very soft SF score of ≤1.5 and not worse than BL, and 2) averagedaily AP score of ≤1.0 and not worse than baseline within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. As used in connection withclinical remission, the phrase “not worse than baseline” means that theaverage daily liquid/very soft SF score or average daily AP score is nothigher than the average daily liquid/very soft SF score or average dailyAP score, respectively, at baseline (i.e., prior to treatment).

In one embodiment, the patient achieves endoscopic remission and/orendoscopic improvement within 2 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the patient achieves endoscopic remissionand/or endoscopic improvement within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, the patient achieves corticosteroid-free remissionwithin 12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof.

In some embodiments, during or by the end of the induction phase (e.g.,lasting for up to 16 weeks, including for 2 weeks, 4 weeks, 6 weeks, 8weeks, 10 weeks, 12 weeks or for 16 weeks), the patient achieves atleast one therapeutic result selected from the group consisting of:

-   1) a CDAI of less than 150 within 16 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   2) a CDAI of less than 150 within 12 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   3) a CDAI of less than 150 within 4 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   4) a decrease in CDAI of greater than or equal to 70 points from    baseline within 16 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   5) a decrease in CDAI of greater than or equal to 70 points from    baseline within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   6) a decrease in CDAI of greater than or equal to 70 points from    baseline within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   7) a clinical remission within 12 weeks of initiating administration    of upadacitinib, or a pharmaceutically acceptable salt or solid    state form thereof,-   8) a clinical remission within 4 weeks of initiating administration    of upadacitinib, or a pharmaceutically acceptable salt or solid    state form thereof,-   9) remission within 16 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic remission within 12 weeks or    within 16 weeks and clinical remission within 16 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof),-   10) remission within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic remission within 12 weeks and    clinical remission within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof),-   11) remission within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic remission within 4 weeks and    clinical remission within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof),-   12) response within 16 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic response within 12 weeks or    within 16 weeks and clinical response within 16 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof),-   13) response within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic response within 12 weeks and    clinical response within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof),-   14) response within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof (i.e., both endoscopic response within 4 weeks and    clinical response within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof),-   15) endoscopic response within 12 weeks or within 16 weeks of    initiating administration of upadacitinib, or a pharmaceutically    acceptable salt or solid state form thereof,-   16) endoscopic response within 4 weeks of initiating administration    of upadacitinib, or a pharmaceutically acceptable salt or solid    state form thereof,-   17) clinical response within 16 weeks of initiating administration    of upadacitinib, or a pharmaceutically acceptable salt or solid    state form thereof,-   18) clinical response within 12 weeks of initiating administration    of upadacitinib, or a pharmaceutically acceptable salt or solid    state form thereof,-   19) clinical response within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   20) clinical response within 2 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof-   21) a change from baseline in fecal calprotectin level within 16    weeks of initiating administration of upadacitinib, or a    pharmaceutically acceptable salt or solid state form thereof,-   22) a change from baseline in fecal calprotectin level within 12    weeks of initiating administration of upadacitinib, or a    pharmaceutically acceptable salt or solid state form thereof,-   23) a change from baseline in fecal calprotectin level within 4    weeks of initiating administration of upadacitinib, or a    pharmaceutically acceptable salt or solid state form thereof,-   24) a change from baseline in hs-CRP (high sensitivity C-reactive    protein) within 16 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   25) a change from baseline in hs-CRP (high sensitivity C-reactive    protein) within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   26) a change from baseline in hs-CRP (high sensitivity C-reactive    protein) within 8 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   27) a change from baseline in hs-CRP (high sensitivity C-reactive    protein) within 4 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   28) a change from baseline in hs-CRP (high sensitivity C-reactive    protein) within 2 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   29) a change in Inflammatory Bowel Disease Questionnaire (IBDQ)    score from baseline within 16 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   30) a change in Inflammatory Bowel Disease Questionnaire (IBDQ)    score from baseline within 12 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   31) a change in Inflammatory Bowel Disease Questionnaire (IBDQ)    score from baseline within 8 weeks of initiating administration of    upadacitinib, or a pharmaceutically acceptable salt or solid state    form thereof,-   32) modified clinical remission within 4 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   33) enhanced clinical response within 8 weeks of initiating    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof and combinations thereof,-   34) steroid-free endoscopic improvement within 4 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   35) steroid-free endoscopic improvement within 8 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   36) steroid-free endoscopic improvement within 16 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   37) steroid-free endoscopic response within 4 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   38) steroid-free endoscopic response within 8 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   39) steroid-free endoscopic response within 16 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   40) steroid-free endoscopic remission within 4 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   41) steroid-free endoscopic remission within 8 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof,-   42) steroid-free endoscopic remission within 16 weeks of    administration of upadacitinib, or a pharmaceutically acceptable    salt or solid state form thereof.

In some embodiments, the patient achieves either a clinical remissionwithin 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, or anendoscopic remission within 12 weeks or within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and further achieves any combination ofadditional therapeutic results selected from the group consisting oftherapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12),13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24), 25), 26),27), 28), 29), and combinations thereof. In one such embodiment, theinduction phase is 16 weeks.

In one embodiment, the induction phase is 12 weeks, and the patientachieves either a clinical remission within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, or an endoscopic remission within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, and further achieves anycombination of additional therapeutic results selected from the groupconsisting of therapeutic results 2), 3), 5), 6), 7), 8), 10), 11), 13),14), 15), 16), 18), 19), 20), 22), 23), 25), 26), 28), 29), andcombinations thereof, wherein the therapeutic result is achieved within12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the induction phase is 4 weeks, and the patientachieves either a clinical remission within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, or an endoscopic remission within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, and further achieves anycombination of additional therapeutic results selected from the groupconsisting of therapeutic results 3), 6), 8), 11), 14), 16), 19), 20),23), 26), 29), and combinations thereof, wherein the therapeutic resultis achieved within 4 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the patient achieves a clinical remission within 12weeks, or within 16 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof,and/or achieves an endoscopic improvement within 12 weeks or within 16weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andfurther achieves any combination of additional therapeutic resultsselected from the group consisting of therapeutic results 1), 2), 3),4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18),19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and combinationsthereof. In one such embodiment, the induction phase is 16 weeks.

In one embodiment, the induction phase is 12 weeks, and the patientachieves a clinical remission within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and/or achieves an endoscopic improvementwithin 12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andfurther achieves any combination of additional therapeutic resultsselected from the group consisting of therapeutic results 2), 3), 5),6), 7), 8), 10), 11), 13), 14), 15), 16), 18), 19), 20), 22), 23), 25),26), 28), 29), and combinations thereof, wherein the therapeutic resultis achieved within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, the induction phase is 16 weeks, and the patientachieves a clinical remission within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and/or achieves an endoscopic improvementwithin 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andfurther achieves any combination of additional therapeutic resultsselected from the group consisting of therapeutic results 1), 2), 3),4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18),19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), and combinationsthereof, wherein the therapeutic result is achieved within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one embodiment, the induction phase is 4 weeks, and the patientachieves a clinical remission within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and/or achieves an endoscopic improvementwithin 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andfurther achieves any combination of additional therapeutic resultsselected from the group consisting of therapeutic results 3), 6), 8),11), 14), 16), 19), 20), 23), 26), 29), and combinations thereof,wherein the therapeutic result is achieved within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, the patient achieves a clinical remission within 4weeks, 12 weeks, or within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, and/or achieves an endoscopic improvement within 4 weeks, 12weeks or within 16 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof, andfurther achieves an additional therapeutic result selected from thegroup consisting of a CDAI of less than 150 within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a CDAI of less than 150within 12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a CDAI ofless than 150 within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic remission within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, an endoscopic remission within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic remissionwithin 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a clinicalresponse within 16 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; aclinical response within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a clinical response within 4 weeks of initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof; a clinical response within 2 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; and combinations thereof. In one suchembodiment, the induction phase is 16 weeks, and the additionaltherapeutic result is selected from the group consisting of a CDAI ofless than 150 within 16 weeks, or within 12 weeks, or within 4 weeks, orwithin 2 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, anendoscopic remission within 16 weeks or within 12 weeks or within 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a clinicalresponse within 16 weeks or within 12 weeks or within 4 weeks, or within2 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andcombinations thereof. In one such embodiment, the induction phase is 12weeks, and the additional therapeutic result is selected from the groupconsisting of a CDAI of less than 150 within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; an endoscopic remission within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a clinical response within12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; andcombinations thereof.

In one embodiment, the additional therapeutic result may further be aclinical remission within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, wherein the patient has an average daily liquid/very soft SFscore of greater than or equal to 2.5 and an average daily AP score ofgreater than or equal to 2.0 at baseline. In one embodiment, when thepatient is one who was taking corticosteroids at baseline but whodiscontinued corticosteroid use during treatment with the JAK1inhibitor, the additional therapeutic result may be selected from thegroup consisting of a CDAI score of less than 150 within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic remissionwithin 12 weeks or within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof and a clinical remission within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a clinical remission within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; and an endoscopic remissionwithin 12 weeks or within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and combinations thereof. In one embodiment, when the patienthas isolated ileal Crohn's disease, the additional therapeutic resultmay further be remission within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one aspect, a patient achieves a CDAI score of less than 150during or by the end of the induction phase.

In one aspect, the patient may achieve an additional therapeutic resultselected from the group consisting of a clinical remission (i.e.,average daily SF score ≤2.8 and not greater than baseline and averagedaily AP score ≤1.0 and not greater than baseline) within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic improvement(i.e., SES-CD score that is greater than a 50% decrease from baseline orat least a 2 point reduction in SES-CD score from baseline or endoscopicremission) within 4 weeks, within 6 weeks, within 12 weeks, or within 16weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; andcombinations thereof.

In one aspect, the patient may achieve an additional therapeutic resultselected from the group consisting of a decrease in CDAI score frombaseline of greater than or equal to 70, and a decrease in CDAI scorefrom baseline of greater than or equal to 100. In one embodiment, theinduction phase is 16 weeks and the decrease in CDAI occurs within 16weeks or within 12 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, the induction phase is 12 weeks and the decrease in CDAIoccurs within 12 weeks of initiating administration of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof.

In one particular embodiment, the induction phase is 16 weeks, and thepatient achieves a clinical remission within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; an endoscopic improvement (i.e., SES-CD scorethat is greater than a 50% decrease from baseline or at least a 2 pointreduction in SES-CD score from baseline, or endoscopic remission) within4 weeks, within 6 weeks, within 12 weeks or within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; and combinations thereof.In another embodiment, the induction phase is 12 weeks, and the patientachieves a clinical remission within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; an endoscopic improvement within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; or combinations thereof.

In one embodiment, the patient is administered upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, for atleast 52 weeks. The administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, mayinclude an induction phase (e.g., an induction phase of up to 16 weeks),and additional weeks (e.g., 36 weeks or longer) of a maintenance phase(discussed hereinafter). In other embodiments, the administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, may include a shorter induction phase (e.g., up to 2 weeks, upto 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, etc.), and a longermaintenance phase (e.g., a 12-week induction phase and a 40 week orlonger maintenance phase). In some such embodiments, the patient mayachieve at least one therapeutic result selected from the groupconsisting of: remission within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; endoscopic remission within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; clinical remission within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, endoscopic improvementwithin 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; responsewithin 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; endoscopicresponse within 52 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof pharm;clinical response within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; CDAI of less than 150 within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a decrease in CDAI of greater than or equal to70 points from baseline within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a change from baseline in fecal calprotectin level within 52weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a changefrom baseline in hs-CRP within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a change in IBDQ score from baseline within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a change inextra-intestinal manifestations (EIMS) from baseline within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; and combinations thereof.

In some embodiment when the patient is administered upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, for atleast 52 weeks, when the patient is one who was taking corticosteroidsat baseline but who discontinued corticosteroid use during treatmentwith the JAK1 inhibitor, the additional therapeutic result may beselected from the group consisting of a CDAI of less than 150 within 52weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; aremission within 52 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; aclinical remission within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and an endoscopic remission within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; and combinations thereof. In one embodiment,when the patient has isolated ileal Crohn's disease, the additionaltherapeutic result may further be remission within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one embodiment, in a method of the present disclosure, a patient isevaluated during or at the end of the induction phase for a therapeuticresult selected from the group consisting of clinical remission,endoscopic improvement, endoscopic remission, endoscopic response,clinical response, CDAI, average daily liquid/very soft SF score,average daily AP score, fecal calprotectin level, hs-CRP, IBDQ score,and combinations thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for clinical remission during or atthe end of the induction phase. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for endoscopic improvementduring or at the end of the induction phase. In one embodiment, in amethod of the present disclosure, a patient is evaluated for endoscopicremission during or at the end of the induction phase.

In one embodiment, the patient is administered at least 14 doses, atleast 28 doses, at least 42 doses, at least 70 doses, or at least 84doses, or at least 112 doses, or at least 140 doses, or at least 168doses, or at least 224 doses, or 70 doses, or 84 doses, or 112 doses, or140 doses, or 168 doses, or 224 doses of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, during theinduction phase.

In one aspect, a certain therapeutic result is maintained by the patientduring the maintenance phase. The maintenance phase may last for anindefinite period of time. In one embodiment, the maintenance phase isat least 36 weeks, including at least 37 weeks, at least 38 weeks, atleast 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks,at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46weeks, at least 47 weeks, or at least 48 weeks. In one embodiment, themaintenance phase is at least 40 additional weeks. In one embodiment,the therapeutic result maintained by the patient during the maintenancephase is selected from the group consisting of clinical remission,endoscopic remission, and combinations thereof. In one embodiment, thetherapeutic result maintained by the patient during the maintenancephase is selected from the group consisting of clinical response,endoscopic improvement, and combinations thereof. In one aspect, apatient maintains a CDAI score of less than 150 during the maintenancephase. In one aspect, a patient maintains a SES-CD that is greater thana 50% decrease versus the patient's baseline SES-CD. In one embodiment,the patient maintains a SES-CD that is at least a 2 point reductionversus the patient's baseline SES-CD. In one embodiment, the therapeuticresult maintained by the patient during the maintenance phase isclinical response. In one embodiment, the therapeutic result maintainedby the patient during the maintenance phase is endoscopic remission.

In one embodiment, in a method of the present disclosure, a patient isevaluated for clinical remission during the maintenance phase. In oneembodiment, a patient is evaluated for endoscopic improvement during themaintenance phase. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for endoscopic remission during themaintenance phase.

In one embodiment, the present disclosure provides a method for treatingan inflammatory disease, in one aspect for treating Crohn's Disease,comprising (a) administering to a patient a dose of a JAK1 inhibitor(e.g., upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof) at week 0 and once daily (QD) thereafter for 16 weeks,wherein the dose is 45 mg QD. In one embodiment, the method furthercomprises (b) administering to the patient additional doses once dailythereafter for at least 36 additional weeks, wherein the dose is 15 mgor 30 mg QD. In one embodiment the dose is administered orally.

In one embodiment, at week 12 (i.e., 12 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for clinical remission(average daily liquid/very soft SF score ≤2.8 and not worse thanbaseline and average daily AP score ≤1.0 and not worse than baseline)and/or for endoscopic remission (SES-CD≤4 (or SES-CD≤2 for patients withisolated ileal CD) and at least a two point reduction in SES-CD versusBL and no subscore >1 in any individual variable used to calculateSES-CD). In one embodiment, at week 16 (i.e., 16 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for clinical remissionand/or for endoscopic remission.

In one embodiment, at week 4 (i.e., 4 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for clinical remission(average daily liquid/very soft SF score ≤2.8 and not worse thanbaseline and average daily AP score ≤1.0 and not worse than baseline)and/or for endoscopic remission (SES-CD≤4 (or SES-CD≤2 for patients withisolated ileal CD) and at least a two point reduction in SES-CD versusBL and no subscore >1 in any individual variable used to calculateSES-CD).

In one embodiment, at week 16 (i.e., 16 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for remission, forexample defined as reaching clinical remission (average dailyliquid/very soft SF score ≤2.8 and not worse than baseline and averagedaily AP score ≤1.0 and not worse than baseline) and endoscopicremission (SES-CD≤4 (or SES-CD≤2 for patients with isolated ileal CD)and at least a two point reduction in SES-CD versus BL and nosubscore >1 in any individual variable used to calculate SES-CD).

In one embodiment, at week 12 (i.e., 12 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for clinical remissionand/or for endoscopic improvement. In one embodiment, at week 16 (i.e.,16 weeks after initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof), a patientis evaluated for clinical remission and/or for endoscopic improvement.

In one embodiment, at week 4 (i.e., 4 weeks after initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof), a patient is evaluated for clinical remissionand/or for endoscopic improvement. In one embodiment, at week 2 (i.e., 2weeks after initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof), a patientis evaluated for clinical remission and/or for endoscopic improvement.

In one embodiment, the present disclosure provides a method for treatingCrohn's disease, comprising (a) administering to a patient a dose of aJAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptable saltor solid state form thereof) at week 0 and once daily thereafter via anoral route, wherein the doses of the JAK1 inhibitor comprise 15 mg, 30mg, or 45 mg QD, or any combination thereof.

In one embodiment, the present disclosure provides a method for treatingCrohn's disease, comprising administering to a patient 15 mg to 45 mg ofa JAK1 inhibitor. In one embodiment, the present disclosure provides amethod for treating Crohn's disease, comprising administering to apatient orally 15 mg of a JAK1 inhibitor QD. In one embodiment, thepresent disclosure provides a method for treating Crohn's disease,comprising administering to a patient orally 30 mg of a JAK1 inhibitorQD. In one embodiment, the present disclosure provides a method fortreating Crohn's disease, comprising administering to a patient orally45 mg of a JAK1 inhibitor QD. In any such embodiments, the JAK1inhibitor may be upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In any such embodiment, the JAK1 inhibitor maybe in a once daily modified release formulation. In any such embodiment,the patient may have moderately to severely active Crohn's disease priorto treatment.

In one embodiment, the administration of a JAK1 inhibitor according tothe present disclosure is further described in the Examples herein belowor in FIG. 1.

In one embodiment, the present disclosure provides a method for treatingCrohn's disease, said method comprising a) administering at least oneinduction dose of a JAK1 inhibitor (e.g., upadacitinib or apharmaceutically acceptable salt or solid state form thereof) to apatient, wherein said induction dose comprises 45 mg of the JAK 1inhibitor. In one aspect, the induction dose is administered orally. Inone aspect, the induction dose is administered QD. In one aspect, theinduction dose is administered for 12 weeks. In one aspect the inductiondose is administered for 16 weeks. In one embodiment, the induction doseis administered for up to 16 weeks, including for 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, or 15 weeks.

In one embodiment, the induction dose comprises 45 mg of the JAK1inhibitor administered QD.

In one embodiment, the JAK1 inhibitor is upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the induction dose is in a once daily modifiedrelease formulation.

In one embodiment, the method further comprises b) administering a firstmaintenance dose of a JAK1 inhibitor (e.g., upadacitinib, orpharmaceutically acceptable salt or solid state form thereof), to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose to the patientonce daily thereafter.

In one embodiment, the first maintenance dose comprises 15 mg to 30 mgof the JAK1 inhibitor. In one aspect, the first maintenance dosecomprises 15 mg or 30 mg of the JAK1 inhibitor. In one aspect, the firstmaintenance dose is smaller than the induction dose. In one aspect, thefirst maintenance dose is administered QD. In one aspect the firstmaintenance dose is 15 mg. In one aspect the first maintenance dose is30 mg. In one aspect, the first maintenance dose is administered orally.In one aspect, the first maintenance dose is in a once daily modifiedrelease formulation.

In one aspect, the at least one additional maintenance dose comprises 15mg to 30 mg of the JAK 1 inhibitor. In one aspect, the at least oneadditional maintenance dose comprises 15 mg or 30 mg. In one aspect, theat least one additional maintenance dose is administered orally. In oneaspect, the at least one additional maintenance dose is administered QD.In one embodiment, the at least one additional maintenance dosecomprises 15 mg of the JAK1 inhibitor administered QD. In oneembodiment, the at least one additional maintenance dose comprises 30 mgof the JAK1 inhibitor administered QD. In one aspect, the at least oneadditional maintenance dose is in a once daily modified releaseformulation.

In any of the foregoing embodiments, the JAK1 inhibitor may beupadacitinib or a pharmaceutically acceptable salt or solid state formthereof.

In one aspect, in any of the foregoing embodiments, the patientmaintains a CDAI score of less than 150.

In one aspect, in any of the foregoing embodiments, the patient is onewho had an inadequate response to or experienced intolerance toconventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agent. Inone aspect, in any of the foregoing embodiments, the patient is one whohad an inadequate response to or experienced intolerance to a previoustreatment with an anti-TNF agent. In one aspect, in any of the foregoingembodiments, the patient is a refractory patient.

In one aspect, in any of the foregoing embodiments, the patient is onewho is naïve to previous treatment with aminosalicylates, acorticosteroid, an immunosuppressant, a biologic agent or an anti-TNFagent.

In one aspect, in any of the foregoing embodiments, the patient is onewho had moderately to severely active Crohn's disease prior to treatmentor administration of the induction dose.

In one embodiment, the present disclosure further provides a method forinducing clinical remission of Crohn's Disease in a patient, said methodcomprising a) administering to the patient at least one induction doseof a JAK1 inhibitor as described above or herein (e.g., upadacitinib ora pharmaceutically acceptable salt or solid state form thereof). In oneembodiment, the induction dose comprises 45 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, an induction dose is administered at week 0 and once daily(QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks,7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mg QD. In oneembodiment, the method further comprises maintaining clinical remissionof Crohn's disease, said method further comprising b) administering afirst maintenance dose of said JAK1 inhibitor to the patient after thelast induction dose is administered and c) administering at least oneadditional maintenance dose to the patient as described above or herein.In one embodiment, the at least one additional maintenance dose isadministered once daily. In one embodiment, the additional maintenancedoses are administered once daily for at least 36 additional weeks,including for at least 37 weeks, at least 38 weeks, at least 39 weeks,at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least47 weeks, or at least 48 weeks. In one embodiment, the additionalmaintenance doses are administered once daily for at least 40 additionalweeks. In one embodiment, the maintenance dose is 15 mg or 30 mg QD. Inone embodiment the induction and maintenance doses are administeredorally. In one embodiment, the patient has a CDAI score of 220 to 450before administration of the first induction dose. In one embodiment,the patient has moderately to severely active Crohn's disease prior toadministration of the first induction dose. In one embodiment, thepatient has had an inadequate response to or experienced intolerance toconventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with a corticosteroid, an immunosuppressant, abiologic agent, and/or an anti-TNF agent. In one embodiment, theclinical remission is achieved within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the clinical remission isachieved within 12 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, the clinical remission is achieved within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, thepatient achieves a CDAI score of less than 150 before administration ofthe first maintenance dose. In one embodiment, the induction andmaintenance doses are in once-daily, modified release formulations.

In one embodiment, the present disclosure provides a method for inducingendoscopic remission of Crohn's disease, the method comprising (a)administering to a patient at least one induction dose of a JAK1inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof), wherein the induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, an induction dose is administered at week 0and once daily (QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mgQD. In one embodiment, the method further comprises maintainingendoscopic remission of Crohn's disease, said method further comprising(b) administering to the patient a first maintenance dose ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, after the last induction dose is administered, and (c)administering at least one additional maintenance dose once dailythereafter. In one embodiment, the additional maintenance doses areadministered once daily for at least 36 additional weeks, including forat least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or atleast 48 weeks. In one embodiment, the additional maintenance doses areadministered once daily for at least 40 additional weeks. In oneembodiment, the maintenance dose is 15 mg or 30 mg QD. In one embodimentthe induction and maintenance doses are administered orally. In oneembodiment, the patient has a CDAI score of 220 to 450 beforeadministration of the first induction dose. In one embodiment, thepatient has moderately to severely active Crohn's disease prior toadministration of the first induction dose. In one embodiment, thepatient has had an inadequate response to or experienced intolerance toconventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic and/or ananti-TNF agent. In one embodiment, the patient is naïve to previoustreatment with a corticosteroid, an immunosuppressant, an anti-TNF agentand/or a biologic agent. In one embodiment, the endoscopic remission isachieved within 12 weeks or within 16 weeks of initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, the endoscopic remission is achievedwithin 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves a CDAI score of less than 150 beforeadministration of the first maintenance dose. In one embodiment, theinduction and maintenance doses are in once-daily, modified releaseformulations.

In one embodiment, the present disclosure further provides a method forinducing endoscopic improvement of Crohn's Disease in a patient, saidmethod comprising a) administering to the patient at least one inductiondose of a JAK1 inhibitor as described above or herein (e.g.,upadacitinib or a pharmaceutically acceptable salt or solid state formthereof). In one embodiment, the induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, an induction dose is administered at week 0and once daily (QD) thereafter for up to 16 weeks (e.g., for 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, or 16 weeks), wherein the dose is 45 mgQD. In one embodiment, the method further comprises maintainingendoscopic improvement of Crohn's disease, said method furthercomprising b) administering a first maintenance dose of said JAK1inhibitor to the patient after the last induction dose is administeredand c) administering at least one additional maintenance dose to thepatient as described above or herein. In one embodiment, the at leastone additional maintenance dose is administered once daily. In oneembodiment, the additional maintenance doses are administered once dailyfor at least 36 additional weeks, including for at least 37 weeks, atleast 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks,at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45weeks, at least 46 weeks, at least 47 weeks, or at least 48 weeks. Inone embodiment, the additional maintenance doses are administered oncedaily for at least 40 additional weeks. In one embodiment, themaintenance dose is 15 mg or 30 mg QD. In one embodiment the inductionand maintenance doses are administered orally. In one embodiment, thepatient has a CDAI score of 220 to 450 before administration of thefirst induction dose. In one embodiment, the patient has moderately toseverely active Crohn's disease prior to administration of the firstinduction dose. In one embodiment, the patient has had an inadequateresponse to or experienced intolerance to a conventional treatment(e.g., aminosalicylates, corticosteroids, immunosuppressants) or to aprevious treatment with a biologic agent and/or an anti-TNF agent. Inone embodiment, the patient is naïve to previous treatment with acorticosteroid, an immunosuppressant, a biologic agent and/or ananti-TNF agent. In one embodiment, the endoscopic improvement isachieved within 16 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, the endoscopic improvement is achieved within 12 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, theendoscopic improvement is achieved within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the patient achieves a CDAIscore of less than 150 before administration of the first maintenancedose. In one embodiment, the induction and maintenance doses are inonce-daily, modified release formulations.

In one embodiment, the present disclosure further provides a method ofmaintaining clinical remission of Crohn's Disease in a patient, saidmethod comprising administering 15 mg or 30 mg of upadacitinib or apharmaceutically acceptable salt form thereof to the patient. In oneembodiment, the upadacitinib or a pharmaceutically acceptable salt formthereof is administered once daily for at least 36 weeks, including forat least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or atleast 48 weeks. In one embodiment the upadacitinib or a pharmaceuticallyacceptable salt form thereof is administered orally. In one embodiment,the patient has had an inadequate response to or experienced intoleranceto a conventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt form thereof is a once-daily, modifiedrelease formulation.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic improvement of Crohn's Disease in a patient, saidmethod comprising administering 15 mg or 30 mg of upadacitinib or apharmaceutically acceptable salt form thereof to the patient. In oneembodiment, the upadacitinib or a pharmaceutically acceptable salt formthereof is administered once daily for at least 36 weeks, including forat least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or atleast 48 weeks. In one embodiment the upadacitinib or a pharmaceuticallyacceptable salt form thereof is administered orally. In one embodiment,the patient has had an inadequate response to or experienced intoleranceto a conventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt form thereof is a once-daily, modifiedrelease formulation.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic remission of Crohn's Disease in a patient, saidmethod comprising administering 15 mg or 30 mg of upadacitinib or apharmaceutically acceptable salt form thereof to the patient. In oneembodiment, the upadacitinib or a pharmaceutically acceptable salt formthereof is administered once daily for at least 36 weeks, including forat least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or atleast 48 weeks. In one embodiment the upadacitinib or a pharmaceuticallyacceptable salt form thereof is administered orally. In one embodiment,the patient has had an inadequate response to or experienced intoleranceto a conventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt form thereof is a once-daily, modifiedrelease formulation.

In one embodiment, the present disclosure further provides a method ofmaintaining remission of Crohn's Disease in a patient, said methodcomprising administering 15 mg or 30 mg of upadacitinib or apharmaceutically acceptable salt form thereof to the patient. In oneembodiment, the upadacitinib or a pharmaceutically acceptable salt formthereof is administered once daily for at least 36 weeks, including forat least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, or atleast 48 weeks. In one embodiment the upadacitinib or a pharmaceuticallyacceptable salt form thereof is administered orally. In one embodiment,the patient has had an inadequate response to or experienced intoleranceto a conventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt form thereof is in a once-daily,modified release formulation.

In one aspect, induction doses for the methods disclosed herein areadministered for 12 weeks in a dose regimen described in Table 3. In oneaspect, induction doses are administered for 16 weeks in a dose regimendescribed in Table 3. In one aspect, maintenance doses are administeredfor 36 weeks or more in a dose regimen described in Table 3. In oneaspect, induction doses for the methods disclosed herein areadministered for 16 weeks and the maintenance doses are administered for36 weeks in a dosing regimen as described in Table 3.

TABLE 3 Doses and Dosing Regimens (BID) Induction Frequency ofMaintenance Frequency of Dose (mg) induction doses dose (mg) maintenancedose 3 BID 3 BID 6 BID 3 BID 6 BID 6 BID 12 BID 3 BID 12 BID 6 BID 12BID 12 BID 24 BID 3 BID 24 BID 6 BID 24 BID 12 BID 24 QD¹ 3 BID 24 QD¹ 6BID 24 QD¹ 12 BID ¹The 24 mg QD dose is two 12 mg tablets administeredsimultaneously.

In one aspect, the induction doses for the methods disclosed herein areadministered for 2 weeks in a dose regimen described in Table 4. In oneaspect, the induction doses for the methods disclosed herein areadministered for 4 weeks in a dose regimen described in Table 4. In oneaspect, induction doses for the methods disclosed herein areadministered for 12 weeks in a dose regimen described in Table 4. In oneaspect, induction doses are administered for 16 weeks in a dose regimendescribed in Table 4. In one aspect, maintenance doses are administeredfor 36 weeks or more in a dose regimen described in Table 4. In oneaspect, induction doses for the methods disclosed herein areadministered for 2 weeks and the maintenance doses are administered for36 or 40 weeks in a dosing regimen as described in Table 4. In oneaspect, induction doses for the methods disclosed herein areadministered for 4 weeks and the maintenance doses are administered for36 or 40 weeks in a dosing regimen as described in Table 4. In oneaspect, induction doses for the methods disclosed herein areadministered for 12 weeks and the maintenance doses are administered for36 or 40 weeks in a dosing regimen as described in Table 4. In oneaspect, induction doses for the methods disclosed herein areadministered for 16 weeks and the maintenance doses are administered for36 or 40 weeks in a dosing regimen as described in Table 4.

TABLE 4 Doses and Dose Regimens (QD) Induction Frequency of MaintenanceFrequency of Dose (mg) induction doses dose (mg) maintenance dose 45 QD15 QD 45 QD 30 QD

In one particular embodiment, the induction dose is 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 30 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In another embodiment, the induction dose is 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 15 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In one embodiment, the maintenance and induction dosesare in once-daily, modified release formulations.

In one embodiment, the present disclosure further provides a method ofinducing clinical remission of Crohn's disease in an adult patienthaving moderately to severely active Crohn's disease, the methodcomprising orally administering once daily to the patient a 45 mg doseof upadacitinib, wherein the patient achieves clinical remission perCrohn's Disease Activity Index (CDAI) at 12 weeks after the first dailyadministration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.In one embodiment, the biologic therapy comprises an anti-TNF agent. Inone embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23. In one embodiment, the biologic therapy comprisesvedolizumab, natalizumab, or ustekinumab.

In one embodiment, the present disclosure further provides a method ofinducing clinical remission of Crohn's disease in an adult patienthaving moderately to severely active Crohn's disease, the methodcomprising orally administering once daily to the patient a 45 mg doseof upadacitinib, wherein the patient achieves clinical remission patientreported outcomes (PROs) at 12 weeks after the first dailyadministration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.In one embodiment, the biologic therapy comprises an anti-TNF agent. Inone embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23. In one embodiment, the biologic therapy comprisesvedolizumab, natalizumab, or ustekinumab.

In one embodiment, the present disclosure further provides a method ofinducing clinical remission of Crohn's disease in an adult patienthaving moderately to severely active Crohn's disease, the methodcomprising orally administering once daily to the patient a 45 mg doseof upadacitinib, wherein the patient achieves clinical remission perpatient reported outcomes (PROs) at 4 weeks after the first dailyadministration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.In one embodiment, the biologic therapy comprises an anti-TNF agent. Inone embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23. In one embodiment, the biologic therapy comprisesvedolizumab, natalizumab, or ustekinumab.

In one embodiment, the present disclosure further provides a method ofinducing endoscopic response of Crohn's disease in an adult patienthaving moderately to severely active Crohn's disease, the methodcomprising orally administering once daily to the patient a 45 mg doseof upadacitinib, wherein the patient achieves endoscopic response at 12weeks after the first daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.In one embodiment, the biologic therapy comprises an anti-TNF agent. Inone embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23. In one embodiment, the biologic therapy comprisesvedolizumab, natalizumab, or ustekinumab.

In one embodiment, the present disclosure further provides a method ofinducing endoscopic remission of Crohn's disease in an adult patienthaving moderately to severely active Crohn's disease, the methodcomprising orally administering once daily to the patient a 45 mg doseof upadacitinib, wherein the patient achieves endoscopic remission at 12weeks after the first daily administration.

In one embodiment, the patient has had an inadequate response orintolerance to biologic therapy prior to the first daily administration.In one embodiment, the biologic therapy comprises an anti-TNF agent. Inone embodiment, the biologic therapy comprises an anti-integrin or ananti-IL12/23. In one embodiment, the biologic therapy comprisesvedolizumab, natalizumab, or ustekinumab.

In one embodiment, the present disclosure further provides a method amethod of treating Crohn's disease in an adult patient having moderatelyto severely active Crohn's disease, the method comprising: a. orallyadministering to the patient an induction dose of 45 mg of upadacitinibonce daily for 12 weeks; and b. orally administering to the patient,after the last induction dose of 45 mg of upadacitinib, a maintenancedose of 15 mg of upadacitinib once daily.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 12 weeks after the administration ofthe initial induction dose of 45 mg of upadacitinib.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 52 weeks after the administration ofthe initial maintenance dose of 15 mg of upadacitinib.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiments, the method is a method of treating Crohn's diseasein an adult patient having refractory or severely active Crohn'sdisease, the method comprising: a) orally administering to the patientan induction dose of 45 mg of upadacitinib once daily for 12 weeks; andb) orally administering to the patient, after the last induction dose of45 mg of upadacitinib, a maintenance dose of 30 mg of upadacitinib oncedaily.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 12 weeks after the administration ofthe initial induction dose of 45 mg of upadacitinib.

In one embodiment, the patient achieves clinical remission per Crohn'sDisease Activity Index (CDAI) at 52 weeks after the administration ofthe initial maintenance dose of 30 mg of upadacitinib.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the present disclosure further provides a method oftreating an adult patient suffering from moderately to severely activeCrohn's disease that is statistically significantly superior to placebo,comprising orally administering once daily to the patient an inductiondose of 45 mg of upadacitinib once daily for 12 weeks, wherein when themethod is used to treat a population of human patients suffering frommoderately to severely active Crohn's disease, a statisticallysignificantly greater percentage of patients achieve clinical remissionper Crohn's Disease Activity Index (CDAI) at 12 weeks after theadministration of the initial induction dose of 45 mg of upadacitinibcompared to a control group of human patients treated with placebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the method further comprises orally administering tothe patient, after the last induction dose of 45 mg of upadacitinib, amaintenance dose of 15 mg of upadacitinib once daily, wherein astatistically significantly greater percentage of patients achieveclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 15 mg ofupadacitinib compared to a control group of human patients treated withplacebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the adult patient is suffering from refractory orseverely active Crohn's disease and the method further comprises orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 30mg of upadacitinib compared to a control group of human patients treatedwith placebo.

In one embodiment, the adult patient had an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the present disclosure further provides a method oftreating adult patients suffering from moderately to severely activeCrohn's disease that is statistically significantly superior to placebo,comprising orally administering once daily to each patient an inductiondose of 45 mg of upadacitinib once daily for 12 weeks, wherein themethod results in a statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) at 12 weeks after the administration of the initial inductiondose of 45 mg of upadacitinib compared to a control group of humanpatients treated with placebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the method further comprises orally administering tothe patient, after the last induction dose of 45 mg of upadacitinib, amaintenance dose of 15 mg of upadacitinib once daily, wherein astatistically significantly greater percentage of patients achieveclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 15 mg ofupadacitinib compared to a control group of human patients treated withplacebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

In one embodiment, the adult patient is suffering from refractory orseverely active Crohn's disease and the method further comprises orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 30mg of upadacitinib of upadacitinib compared to a control group of humanpatients treated with placebo.

In one embodiment, the adult patients have an inadequate response orintolerance to a previous treatment with an anti-TNF agent.

In one embodiment, the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.

IV. Methods of Treatment of Ulcerative Colitis

In one aspect, the present disclosure is directed to methods for thetreatment of ulcerative colitis. In one aspect, the present disclosureprovides methods for treating ulcerative colitis, in particular methodscomprising administering a JAK1 inhibitor to a patient in certainamounts and/or at certain intervals. In one aspect, the JAK1 inhibitoris upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof.

In one aspect, the present disclosure provides a JAK1 inhibitor for usein the treatment of ulcerative colitis, by administration in certainamounts and/or at certain intervals as described herein. In one aspect,the JAK1 inhibitor is upadacitinib or a pharmaceutically acceptable saltor solid state form thereof.

In one aspect, the present disclosure provides for the use of a JAK1inhibitor for the preparation of a medicament for the treatment ofulcerative colitis, by administration in certain amounts and/or atcertain intervals as described herein. In one aspect, the JAK1 inhibitoris upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof.

In one aspect, the present disclosure is directed to methods forinducing clinical remission and/or endoscopic remission of ulcerativecolitis. In one aspect, the present disclosure provides methods forinducing clinical remission and/or endoscopic remission of ulcerativecolitis, in particular methods comprising administering a JAK1 inhibitorto a patient in certain amounts and/or at certain intervals as describedherein. In one aspect, the present disclosure is further directed tomethods for inducing clinical remission wherein the patient has a SFscore ≤1, RBS of 0 and endoscopy score ≤1 at week 48 followingadministration of the JAK1 inhibitor. In one aspect the patient achievesclinical remission per Full Mayo score ≤2 with no subscore >1) plusfecal calprotectin below 150 mg/kg at Week 8 following administration ofthe JAK1 inhibitor. In one aspect the patient has an increase of IBDQ≥16from baseline at week 8 following administration of the JAK1 inhibitor.In one aspect, the patient has a RBS≥1 or an absolute RBS≤1 at week 8following administration of the JAK1 inhibitor. In one aspect, thepatient has a SF subscore ≤1 at week 8 following administration of theJAK1 inhibitor. In one aspect, the patient achieves a RBS of 0 at week8. In one aspect the patient achieves a fecal calprotectin below 150mg/kg at week 8 following administration of the JAK1 inhibitor. In oneaspect the patient achieves histologic improvement at week 8 followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof.

In one aspect, the present disclosure provides a JAK1 inhibitor for usein inducing clinical remission of ulcerative colitis by administrationin certain amounts and/or at certain intervals as described herein. Inone aspect, the present disclosure provides a JAK1 inhibitor for use ininducing clinical remission and/or clinical response and/or endoscopicimprovement and/or endoscopic remission of ulcerative colitis byadministration in certain amounts and/or at certain intervals asdescribed herein. In one aspect, the JAK1 inhibitor is upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

In one aspect, the present disclosure provides for the use of a JAK1inhibitor for the preparation of a medicament for inducing clinicalremission of ulcerative colitis by administration in certain amountsand/or at certain intervals as described herein. In one aspect, thepresent disclosure provides for the use of a JAK1 inhibitor for thepreparation of a medicament for inducing clinical remission and/orclinical response and/or endoscopic improvement and/or endoscopicremission of ulcerative colitis by administration in certain amountsand/or at certain intervals as described herein. In one aspect, the JAK1inhibitor is upadacitinib or a pharmaceutically acceptable salt or solidstate form thereof.

In one particular aspect, the disease is moderately to severely activeulcerative colitis. In one aspect, in the context of the presentdisclosure, a patient is naïve to, or was previously treated withimmunosuppressants (e.g., methotrexate), aminosalicylate,corticosteroid, and/or a biologic agent (e.g., vedolizumab, ustekinumab,natalizumab, etc.). In one aspect, the patient is naïve to, or waspreviously treated with an anti-TNF therapy (e.g., infliximab,adalimumab, certolizumab pegol, golimumab, etc.). In one aspect, in thecontext of a method of the present disclosure a patient was previouslytreated with one, two, three or more TNF antagonist(s) (also referred toherein as anti-TNF agents). In one embodiment, the patient is a patientwho had an inadequate response with, lost response, or was intolerant toa TNF antagonist. In one aspect, in the context of a method of thepresent disclosure a patient was previously treated with one, two, threeor more biologic agent(s). In one embodiment, the patient is a patientwho had an inadequate response with, lost response, or was intolerant toa biologic agent. In one embodiment, the patient is a patient who had aninadequate response with, lost response, or was intolerant to a TNFantagonist, aminosalicylates, corticosteroids, immunosuppressants,and/or a biologic agent. In one embodiment, the patient is a refractorypatient who has moderately to severely active ulcerative colitis. In oneembodiment, the patient is either naïve to or has stopped usingcorticosteroids prior to treatment with the JAK1 inhibitor.

Disease severity for ulcerative colitis may be measured using a varietyof indexes, including the Mayo Scoring System for Assessment ofUlcerative Colitis Activity (“Full Mayo”), the Adapted Mayo Score(consisting of the stool frequency subscore, rectal bleeding subscoreand endoscopy subscore of the Full Mayo), the Ulcerative ColitisEndoscopic Index of Severity (UCEIS) score system, the InflammatoryBowel Disease Questionnaire (IBDQ), the Work Productivity and ActivityImpairment Questionnaire for Ulcerative Colitis (version 2.0) (WPAI:UC),the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L), the ShortForm 36 Item (SF-36) Health Survey (version 2), the FunctionalAssessment of Chronic Illness Therapy-Fatigue (FACIT-F), UlcerativeColitis Symptoms Questionnaire (UC-SQ), and the Patient GlobalImpression of Change (PGIC).

The Mayo Scoring System for Assessment of Ulcerative Colitis Activity,shown below, is a composite of the following subscores: Stool FrequencySubscore, Rectal Bleeding Subscore (RBS), Endoscopy Subscore, andPhysician's Global Assessment Subscore.

TABLE 5 Mayo Scoring System for Assessment of Ulcerative ColitisActivity (Full Mayo) Stool frequency Subscore* 0 = Normal number ofstools for this subject 1 = 1-2 stools more than normal 2 = 3-4 stoolsmore than normal 3 = 5 or more stools more than normal *Each patientserves as his or her own control to establish normal stool frequency andthe degree of abnormal stool frequency. Rectal bleeding Subscore** 0 =No blood seen 1 = Streaks of blood with stool less than half the time 2= Obvious blood with stool most of the time 3 = Blood alone passed **Thedaily bleeding score represents the most severe bleeding of the day.Endoscopy Subscore: Findings of flexible sigmoidoscopy 0 = Normal orinactive disease 1 = Mild disease (erythema, decreased vascular pattern,mild friability) 2 = Moderate disease (marked erythema, absent vascularpattern, friability, erosions) 3 = Severe disease (spontaneous bleeding,ulceration) Physician's Global Assessment Subscore*** 0 = Normal(Subscores are 0) 1 = Mild disease (Subscores are mostly 1's) 2 =Moderate disease (Subscores are 1 to 2) 3 = Severe disease (Subscoresare 2 to 3) ***The physician's global assessment acknowledges the threeother subscores, the subject's daily record of abdominal discomfort andfunctional assessment, and other observations such as physical findings,and the subject's performance status.

The IBDQ is a well-known 32 item validated questionnaire that assesses apatient's inflammatory bowel disease symptoms, general well-being, andmood, and may be used as a tool to evaluate a patient's quality of life(Guyatt, et al., Gastroenterology, 1989, 96:804-810). The IBDQ questionsand answer options are set forth below in Table 6.

TABLE 6 IBDQ Question Answer Options 1. How frequent have your bowel 1Bowel movements as or more frequent than they movements been during thelast two have ever been weeks? 2 Extremely Frequent 3 Very frequent 4Moderate increase in frequency of bowel movements 5 Some increase infrequency of bowel movements 6 Slight increase in frequency of bowelmovements 7 Normal, no increase in frequency of bowel movements 2. Howoften has the feeling of fatigue or 1 All of the time of being tired andworn out been a 2 Most of the time problem for you during the last 2weeks? 3 A good bit of the time 4 Some of the time 5 A little of thetime 6 Hardly any of the time 7 None of the time 3. How often during thelast 2 weeks 1 All of the time have you felt frustrated, impatient, or 2Most of the time restless? 3 A good bit of the time 4 Some of the time 5A little of the time 6 Hardly any of the time 7 None of the time 4. Howoften during the last 2 weeks 1 All of the time have you been unable toattend school or 2 Most of the time do your work because of your bowel 3A good bit of the time problem? 4 Some of the time 5 A little of thetime 6 Hardly any of the time 7 None of the time 5. How much of the timeduring the last 1 All of the time 2 weeks have your bowel movements 2Most of the time been loose? 3 A good bit of the time 4 Some of the time5 A little of the time 6 Hardly any of the time 7 None of the time 6.How much energy have you had 1 No energy at all during the last 2 weeks?2 Very little energy 3 A little energy 4 Some energy 5 A moderate amountof energy 6 A lot of energy 7 Full of energy 7. How often during thelast 2 weeks did 1 All of the time you feel worried about thepossibility of 2 Most of the time needing to have surgery because ofyour 3 A good bit of the time bowel problem? 4 Some of the time 5 Alittle of the time 6 Hardly any of the time 7 None of the time 8. Howoften during the last 2 weeks 1 All of the time have you had to delay orcancel a social 2 Most of the time engagement because of your bowel 3 Agood bit of the time problem? 4 Some of the time 5 A little of the time6 Hardly any of the time 7 None of the time 9. How often during the last2 weeks 1 All of the time have you been troubled by cramps in your 2Most of the time abdomen? 3 A good bit of the time 4 Some of the time 5A little of the time 6 Hardly any of the time 7 None of the time 10. Howoften during the last 2 weeks 1 All of the time have you felt generallyunwell? 2 Most of the time 3 A good bit of the time 4 Some of the time 5A little of the time 6 Hardly any of the time 7 None of the time 11. Howoften during the last 2 weeks 1 All of the time have you been troubledbecause of fear of 2 Most of the time not finding a washroom? 3 A goodbit of the time 4 Some of the time 5 A little of the time 6 Hardly anyof the time 7 None of the time 12. How much difficulty have you had, 1Agreat deal of difficulty; activities made impossible as a result of yourbowel problems, doing 2 A lot of difficulty leisure or sports activitiesyou would have 3 A fair bit of difficulty liked to have done during thelast 2 4 Some difficulty weeks? 5 A little difficulty 6 Hardly anydifficulty 7 No difficulty; the bowel problems did not limit sports orleisure activities 13. How often during the last 2 weeks 1 All of thetime have you been troubled by pain in the 2 Most of the time abdomen? 3A good bit of the time 4 Some of the time 5 A little of the time 6Hardly any of the time 7 None of the time 14. How often during the last2 weeks 1 All of the time have you had problems getting a good 2 Most ofthe time night's sleep, or been troubled by waking 3 A good bit of thetime up during the night? 4 Some of the time 5 A little of the time 6Hardly any of the time 7 None of the time 15. How often during the last2 week 1 All of the time shave you felt depressed or discouraged? 2 Mostof the time 3 A good bit of the time 4 Some of the time 5 A little ofthe time 6 Hardly any of the time 7 None of the time 16. How oftenduring the last 2 weeks 1 All of the time have you had to avoidattending events 2 Most of the time where there was no washroom close at3 A good bit of the time hand? 4 Some of the time 5 A little of the time6 Hardly any of the time 7 None of the time 17. Overall, in the last 2weeks, how 1 A major problem much of a problem have you had with 2 A bigproblem passing large amounts of gas? 3 A significant problem 4 Sometrouble 5 A little trouble 6 Hardly any trouble 7 No trouble 18.Overall, in the last 2 weeks, how 1 A major problem much of a problemhave you had 2 A big problem maintaining or getting to, the weight you 3A significant problem would like to be at? 4 Some trouble 5 A littletrouble 6 Hardly any trouble 7 No trouble 19. Many patients with bowelproblems 1 All of the time often have worries and anxieties related 2Most of the time to their illness. These include worries 3 A good bit ofthe time about getting cancer, worries about never 4 Some of the timefeeling any better, and worries about 5 A little of the time having arelapse. In general, how often 6 Hardly any of the time during the last2 weeks have you felt 7 None of the time worried or anxious? 20. Howmuch of the time during the last 1 All of the time 2 weeks have you beentroubled by a 2 Most of the time feeling of abdominal bloating? 3 A goodbit of the time 4 Some of the time 5 A little of the time 6 Hardly anyof the time 7 None of the time 21. How often during the last 2 weeks 1None of the time have you felt relaxed and free of tension? 2 A littleof the time 3 Some of the time 4 A good bit of the time 5 Most of thetime 6 Almost all of the time 7 All of the time 22. How much of the timeduring the last 1 All of the time 2 weeks have you had a problem with 2Most of the time rectal bleeding with your bowel 3 A good bit of thetime movements? 4 Some of the time 5 A little of the time 6 Hardly anyof the time 7 None of the time 23. How much of the time during the last1 All of the time 2 weeks have you felt embarrassed as a 2 Most of thetime result of your bowel problem? 3 A good bit of the time 4 Some ofthe time 5 A little of the time 6 Hardly any of the time 7 None of thetime 24. How much of the time during the last 1 All of the time 2 weekshave you been troubled by a 2 Most of the time feeling of having to goto the bathroom 3 A good bit of the time even though your bowels wereempty? 4 Some of the time 5 A little of the time 6 Hardly any of thetime 7 None of the time 25. How much of the time during the last 1 Allof the time 2 weeks have you felt tearful or upset? 2 Most of the time 3A good bit of the time 4 Some of the time 5 A little of the time 6Hardly any of the time 7 None of the time 26. How much of the timeduring the last 1 All of the time 2 weeks have you been troubled by 2Most of the time accidental soiling of your underpants? 3 A good bit ofthe time 4 Some of the time 5 A little of the time 6 Hardly any of thetime 7 None of the time 27. How much of the time during the last 1 Allof the time 2 weeks have you felt angry as a result of 2 Most of thetime your bowel problem? 3 A good bit of the time 4 Some of the time 5 Alittle of the time 6 Hardly any of the time 7 None of the time 28. Towhat extent has your bowel 1 No sex as a result of bowel disease problemlimited sexual activity during the 2 Major limitation as a result ofbowel disease last 2 weeks? 3 Moderate limitation as a result of boweldisease 4 Some limitation as a result of bowel disease 5 A littlelimitation as a result of bowel disease 6 Hardly any limitation as aresult of bowel disease 7 No limitation as a result of bowel disease 29.How much of the time during the last 1 All of the time 2 weeks have youbeen troubled by 2 Most of the time nausea or feeling sick to yourstomach? 3 A good bit of the time 4 Some of the time 5 A little of thetime 6 Hardly any of the time 7 None of the time 30. How much of thetime during the last 1 All of the time 2 weeks have you felt irritable?2 Most of the time 3 A good bit of the time 4 Some of the time 5 Alittle of the time 6 Hardly any of the time 7 None of the time 31. Howoften during the past 2 weeks 1 All of the time have you felt a lack ofunderstanding 2 Most of the time from others? 3 A good bit of the time 4Some of the time 5 A little of the time 6 Hardly any of the time 7 Noneof the time 32. How satisfied, happy, or leased have 1 Verydissatisfied, unhappy most of the time you been with your personal lifeduring 2 Generally dissatisfied, unhappy the past 2 weeks? 3 Somewhatdissatisfied, unhappy 4 Generally satisfied, pleased 5 Satisfied most ofthe time, happy 6 Very satisfied most of the time, happy 7 Extremelysatisfied, could not have been more happy or pleased

The Work Productivity and Activity Impairment Questionnaire forUlcerative Colitis (WPAI:UC) and Crohn's Disease (WPAI:CD) assesses theimpact of the condition on work productivity losses and impairment indaily activity. WPAI:UC has six items covering four domains: Absenteeism(work time missed), measured as the number of hours missed from work inthe past 7 days due to a condition related problem. Scores are expressedas impairment percentages, adjusting for hours actually worked accordingto the WPAI:UC or WPAI:CD scoring algorithm; Presenteeism (impairment atwork/reduced on-the-job effectiveness), measured as the impact of thecondition on productivity while at work (i.e., reduced amount or kind ofwork, or not as focused as usual). Responses are recorded on a 0-10Likert scale (where, 0=no effect of UC or CD on work and 10=severeimpact of UC or CD while at work); productivity loss (overall workimpairment), measured as the sum of hours missed due to condition i.e.,absenteeism and number of hours worked with impairment i.e., product ofnumber of hours worked and presenteeism; and activity impairment (i.e.,activities other than paid work like work around house, cleaning,shopping, traveling, studying), recorded and scored in the same way aspresenteeism. Higher numbers indicate greater impairment and lessproductivity. The WPAI:UC/WPAI:CD questions and answer options are setforth in Table 7.

TABLE 7 WPAI:UC* and WPAI:CD Questions Answer Options 1. Are youcurrently employed (working for pay)? No or yes If no, skip to question6. 2. During the past seven days, how many hours did you miss Number ofhours from work because of problems associated with your ulcerativecolitis? Include hours you missed on sick days, times you went in late,left early, etc., because of your ulcerative colitis. Do not includetime you missed to participate in this study. 3. During the past sevendays, how many hours did you miss Number of hours from work because ofany other reason, such as vacation, holidays, time off to participate inthis study? 4. During the past seven days, how many hours did youactually Number of hours (if 0, skip to work? question 6) 5. During thepast seven days, how much did your ulcerative Select number on a scaleof 0 (UC colitis affect your productivity while you were working? had noeffect on work) to 10 (UC Think about days you were limited in theamount or kind of completely prevented me from work you could do, daysyou accomplished less than you would working), representing how muchlike, or days you could not do your work as carefully as usual.ulcerative colitis affected If ulcerative colitis affected your workonly a little, choose a low productivity while at work number. Choose ahigh number if ulcerative colitis affected your work a great deal. 6.During the past 7 days, how much did your ulcerative colitis Selectnumber on a scale of 0 (UC affect your ability to do your regular dailyactivities, other than had no effect on daily activities) to work at ajob? 10 (UC completely prevented me Regular activities means usualactivities, such as work around from doing daily activities), the house,shopping, childcare, exercising, studying, etc. representing how muchulcerative Consider times you were limited in the amount or kind ofcolitis affected ability to do activities you could do and times youaccomplished less than regular daily activities, other than you wouldlike. If ulcerative colitis affected your activities only work at a joba little, choose a low number. Choose a high number if ulcerativecolitis affected your activities a great deal. *Questions 2-7 are aboutthe previous seven days, not including the day the questionnaire iscompleted.

The European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) is astandardized non-disease specific instrument for describing and valuinghealth-related quality of life. The EQ-5D-5L consists of 5 dimensions:mobility, self-care, usual activity, pain/discomfort, andanxiety/depression. Each dimension has 5 levels: no problem, slightproblem, moderate problem, severe problem or unable to do the activity.It also contains a Visual Analogue Scale (VAS). Subjects are asked toindicate the level that describes their current level of function orexperience for each dimension. As a measure of health status, itprovides a descriptive profile and can be used to generate a singleindex value for health status, where full health is equal to 1 and deathis equal to 0. The VAS records the subject's assessment of his/her ownhealth along a vertical 20 cm line, which has health state scoresbetween 0 and 100. The EQ-5D-5L questions and answer options are setforth in Table 8.

TABLE 8 EQ-5D-5L Questionnaire Dimension Answer Options Score Mobility Ihave no problems walking MB1 I have slight problems walking MB2 I havemoderate problems walking MB3 I have severe problems walking MB4 I amunable to walk MB5 Self-Care I have no problems washing or dressing SC1myself I have slight problems washing or dressing SC2 myself I havemoderate problems washing or dressing SC3 myself I have severe problemswashing or dressing SC4 myself I am unable to wash or dress myself SC5Usual I have no problems doing my usual activities UA1 Activities* Ihave slight problems doing my usual UA2 activities I have moderateproblems doing my usual UA3 activities I have severe problems doing myusual UA4 activities I am unable to do my usual activities UA5 Pain/ Ihave no pain or discomfort PD1 Discomfort I have slight pain ordiscomfort PD2 I have moderate pain or discomfort PD3 I have severe painor discomfort PD4 I have extreme pain or discomfort PD5 Anxiety/ I amnot anxious or depressed AD1 Depression I am slightly anxious ordepressed AD2 I am moderately anxious or depressed AD3 I am severelyanxious or depressed AD4 I am extremely anxious or depressed AD5 Howgood We would like to know how good or bad your or bad is health isTODAY. your health This scale is numbered from 0 to 100. today? 100means the best health you can imagine. 0 means the worst health you canimagine. Mark an X on the scale to indicate how your health is TODAY.Now, please write the number you marked on the scale in the box below.*E.g., work, study, housework, family or leisure activities

The SF-36 questionnaire is a self-administered multi-domain scale with36 items. Eight subscales cover a range of functioning: physicalfunctioning (PF), role-physical (RP), bodily pain (BP), general health(GH), vitality (VT), social functioning (SF), role-emotional (RE), andmental health (MH). The scoring yields a physical component score, amental component summary score, and subscale scores. Higher scoresrepresent better outcomes. The concepts measured by the SF-36 are notspecific to any age, disease, or treatment group, allowing comparison ofrelative burden of different diseases and the benefit of differenttreatments. The SF-36 questions and answer options are set forth belowin Table 9.

TABLE 9 SF-36 Health Survey Function - Question number Question AnswerOptions GH - 1 In general, would you say your health is: Excellent Verygood Good Fair Poor Compared to one year ago, how would you rate Muchbetter now than one year ago your health in general now? Somewhat betternow than one year ago About the same as one year ago Somewhat worse nowthan one year ago Much worse now than one year ago PF - 1¹ Does yourhealth now limit you in vigorous Yes, limited a lot activities, such asrunning, lifting heavy objects, Yes, limited a little participating instrenuous sports? If so, how much? No, not limited at all PF - 2¹ Doesyour health now limit you in moderate Yes, limited a lot activities,such as moving a table, pushing a Yes, limited a little vacuum cleaner,bowling, or playing golf? If so, No, not limited at all how much? PF -3¹ Does your health now limit you in lifting or Yes, limited a lotcarrying groceries? If so, how much? Yes, limited a little No, notlimited at all PF - 4¹ Does your health now limit you in climbingseveral Yes, limited a lot flights of stairs? If so, how much? Yes,limited a little No, not limited at all PF - 5¹ Does your health nowlimit you in climbing one Yes, limited a lot flight of stairs? If so,how much? Yes, limited a little No, not limited at all PF - 6¹ Does yourhealth now limit you in bending, Yes, limited a lot kneeling, orstooping? If so, how much? Yes, limited a little No, not limited at allPF - 7¹ Does your health now limit you in walking more Yes, limited alot than a mile? If so, how much? Yes, limited a little No, not limitedat all PF - 8¹ Does your health now limit you in walking several Yes,limited a lot hundred yards? If so, how much? Yes, limited a little No,not limited at all PF - 9¹ Does your health now limit you in walking oneYes, limited a lot hundred yards? If so, how much? Yes, limited a littleNo, not limited at all PF - 10¹ Does your health now limit you inbathing or Yes, limited a lot dressing yourself? If so, how much? Yes,limited a little No, not limited at all RP - 1² Cut down on the amountof time you spent on work All of the time or other activities as aresult of your physical health Most of the time Some of the time Alittle of the time None of the time RP - 2² Accomplished less than youwould like as a result All of the time of your physical health Most ofthe time Some of the time A little of the time None of the time RP - 3²Were limited in the kind of work or other activities All of the time asa result of your physical health Most of the time Some of the time Alittle of the time None of the time RP - 4² Had difficulty performingthe work or other All of the time activities as a result of yourphysical health (for Most of the time example, it took extra effort)Some of the time A little of the time None of the time RE - 1² Cut downon the amount of time you spent on work All of the time or otheractivities as a result of any emotional Most of the time problems (suchas feeling depressed or anxious) Some of the time A little of the timeNone of the time RE - 2² Accomplished less than you would like as aresult All of the time of any emotional problems (such as feeling Mostof the time depressed or anxious) Some of the time A little of the timeNone of the time RE - 3² Did work or other activities less carefullythan usual All of the time as a result of any emotional problems (suchas Most of the time feeling depressed or anxious) Some of the time Alittle of the time None of the time SF - 1 During the past 4 weeks, towhat extent has your Not at all physical health or emotional problemsinterfered Slightly with your normal social activities with family,Moderately friends, neighbors, or groups? Quite a bit Extremely BP - 1How much bodily pain have you had during the past None 4 weeks? Verymild Mild Moderate Severe Very severe BP - 2 During the past 4 weeks,how much did pain Not at all interfere with your normal work (includingboth A little bit work outside the home and housework)? Moderately Quitea bit Extremely VT - 1³ How much of the time during the past 4 weeks didAll of the time you feel full of life? Most of the time Some of the timeA little of the time None of the time MH - 1³ How much of the timeduring the past 4 weeks have All of the time you been very nervous? Mostof the time Some of the time A little of the time None of the time MH -2³ How much of the time during the past 4 weeks have All of the time youfelt so down in the dumps that nothing could Most of the time cheer youup? Some of the time A little of the time None of the time MH - 3³ Howmuch of the time during the past 4 weeks have All of the time you feltcalm and peaceful? Most of the time Some of the time A little of thetime None of the time VT - 2³ How much of the time during the past 4weeks did All of the time you have a lot of energy? Most of the timeSome of the time A little of the time None of the time MH - 4³ How muchof the time during the past 4 weeks have All of the time you feltdownhearted and depressed? Most of the time Some of the time A little ofthe time None of the time VT - 3³ How much of the time during the past 4weeks did All of the time you feel worn out? Most of the time Some ofthe time A little of the time None of the time MH - 5³ How much of thetime during the past 4 weeks have All of the time you been happy? Mostof the time Some of the time A little of the time None of the time VT -4³ How much of the time during the past 4 weeks did All of the time youfeel tired? Most of the time Some of the time A little of the time Noneof the time SF - 2 During the past 4 weeks, how much of the time has Allof the time your physical health or emotional problems Most of the timeinterfered with your social activities (like visiting Some of the timewith friends, relatives, etc.)? A little of the time None of the timeGH - 2⁴ I seem to get sick a little easier than other people. Definitelytrue Mostly true Don't know Mostly false Definitely false GH - 3⁴ I amas healthy as anybody I know. Definitely true Mostly true Don't knowMostly false Definitely false GH - 4⁴ I expect my health to get worse.Definitely true Mostly true Don't know Mostly false Definitely falseGH - 5⁴ My health is excellent. Definitely true Mostly true Don't knowMostly false Definitely false ¹Instructions: The following question isabout activities you might do during a typical day ²Instructions: Duringthe past 4 weeks, how much of the time have you had any of the followingproblems with your work or other regular daily activities?³Instructions: This question is about how you feel and how things havebeen with you during the past 4 weeks. Please give the one answer thatcomes closest to the way you have been feeling. ⁴Instructions: How TRUEor FALSE is the following statement for you?

The Functional Assessment of Chronic Illness Therapy (FACIT) system is acollection of quality of life (QOL) questionnaires targeted to themanagement of cancer and other chronic illnesses. The FACIT fatigue(FACIT-F) questionnaire was developed to assess fatigue associated withanemia. It consists of 13 fatigue-related questions. The responses tothe 13 items on the FACIT fatigue questionnaire are each measured on a4-point Likert scale. The responses to the answers are the following:(i) not at all: 0 points; (ii) a little bit: 1 point; (iii) somewhat: 2points; (iv) quite a bit: 3 points; and (v) very much: 4 points. Thus,the total score ranges from 0 to 52. High scores represent less fatigue.The FACIT-F questions and answer options are set forth below in Table10.

TABLE 10 FACIT-F Questionnaire Answer Question Options I feel fatigued .. . 0 Not at all I feel weak all over . . . 1 A little bit I feellistless (“washed out”) . . . 2 Somewhat I feel tired . . . 3 Quite abit I have trouble starting things because I am tired . . . 4 Very muchI have trouble finishing things because I am tired . . . I have energy .. . I am able to do my usual activities . . . I need to sleep during theday . . . I am too tired to eat . . . I need help doing my usualactivities . . . I am frustrated by being too tired to do the things Iwant to do . . . I have to limit my social activity because I am tired .. .

The Ulcerative Colitis Symptoms Questionnaire (UC-SQ) is a UC-specificinstrument composed of 17 Likert-type items. UC-SQ was developed toassess UC related gastrointestinal and non-gastrointestinal symptomssuch as frequent bowel movements, abdominal discomfort, nausea, loss ofappetite, pain, and anemia along with the impact on patients' sleep.Each question can be answered using Likert-type options such as (i) Notat all: 0 points; (ii) A little bit: 1 point; (iii) Somewhat: 2 points;(iv) Quite a bit: 3 points; and (v) Very much: 4 points based on how thepatient felt during the past week (i.e., 7 days). The total score rangescan vary from 0 to 68 with lower scores indicating improvement. TheUC-SQ questions and answer options are set forth below in Table 11.

TABLE 11 UC-SQ Questionnaire Answer Question Options During the pastweek, were your bowel movements more Not at all frequent than usual? Alittle bit During the past week, did you pass gas more than usual?Somewhat During the past week, did you have abdominal pain? Quite a bitDuring the past week, did you have rectal pain? Very During the pastweek, did you have cramping? much During the past week, have you felttired or lacking energy? During the past week, did you feel nauseated?During the past week, did you experience loss of appetite? During thepast week, did you have joint pain? During the past week, did you havedifficulty sleeping? During the past week, did you experience bloating?During the past week, did you have diarrhea? During the past week, didyou pass blood or have blood in your stool? During the past week, didyou have mucus in your stool? During the past week, were youconstipated? During the past week, did you feel that you needed to havea bowel movement - even when your bowels were empty? During the pastweek, did you experience a sudden or intense need to have a bowelmovement?

The Patient Global Impression of Change (PGIC) is a self-administeredinstrument that assesses change in the overall symptoms due toUlcerative Colitis. The PGIC is one item in which subjects are asked torate overall improvement since start of the treatment. Patients areasked the question “Compared to before your treatment began, how wouldyou rate the change in your overall symptoms due to your ulcerativecolitis?”, and rate their change as “Very much improved,” “Muchimproved,” “Minimally improved”, “No change,” “Minimally worse,” “Muchworse” and “Very much worse”.

In one aspect, the patient to be treated has moderately to severelyactive ulcerative colitis. Moderately to severely active ulcerativecolitis is characterized by an Adapted Mayo score of 5 to 9 points andan endoscopy subscore of 2 to 3.

In one embodiment, the patient is a patient who had an inadequateresponse with, lost response, or was intolerant to a conventionaltherapy (e.g., aminosalicylate, corticosteroids, immunosuppressants), orto a biologic agent. In one embodiment, the patient is a patient who hadan inadequate response with, lost response, or was intolerant tobiologic therapies. Examples of such biologic therapies includeinfliximab, adalimumab, vedolizumab, golimumab, ustekinumab andcertolizumab pegol. Criteria for determining if a patient has had aninadequate response to, lost response, or experienced intolerance toprevious treatment with corticosteroids, immunosuppressants, and/or abiologic therapy are defined below:

Corticosteroids:

-   1) Signs and symptoms of persistently active disease despite a    history of at least one induction regimen that included a dose    equivalent to prednisone ≥40 mg/day orally for 3 to 4 weeks or    intravenously for 1 week, or-   2) Unable to taper corticosteroid to below a dose equivalent to    prednisone 10 mg daily orally without recurrent active disease, or-   3) History of intolerance to corticosteroids (including, but no    limited to Cushing's syndrome, osteopenia/osteoporosis,    hyperglycemia, insomnia, infection).

Immunosuppressants:

-   1) Signs and symptoms of persistently active disease despite a    history of at least one 90-day regimen of oral azathioprine (≥1.5    mg/kg/day; for subjects in Japan and China only: ≥1.0 mg/kg/day),    6-mercaptopurine (≥1 mg/kg/day [for subjects in Japan and China    only: ≥0.6 mg/kg/day, rounded to the nearest available tablet of    half tablet formulation]; or a documented 6-TGN level of 230-450    pmol/8×10⁸ RBC or higher on the current dosing regimen), injectable    methotrexate (MTX≥15 mg/week subcutaneous [SC] or intramuscular), or    tacrolimus (for subjects in Japan only: documented trough level of    5-10 ng/mL), or-   2) History of intolerance to at least one immunosuppressant    (including, but not limited to nausea/vomiting, abdominal pain,    pancreatitis, liver enzyme abnormalities, lymphopenia, infection)

Biologic Agents for UC:

-   1) Signs and symptoms of persistently active disease despite a    history of any of the following:    -   a. at least one 6-week induction regimen of infliximab (≥5 mg/kg        intravenous [IV] at 0, 2 and 6 weeks),    -   b. at least one 4-week induction regimen of adalimumab (one 160        mg SC dose followed by one 80 mg SC dose [or one 80 mg SC dose,        in countries where this dosing regimen is allowed] followed by        one 40 mg SC dose at least 2 weeks apart),    -   c. at least one 2-week induction regimen of golimumab (one 200        mg SC dose followed by one 100 mg SC dose at least 2 weeks        apart),    -   d. at least one 6-week induction regimen of vedolizumab (300 mg        IV at 0, 2 and 6 weeks), or-   2) Recurrence of symptoms during scheduled maintenance dosing    following prior clinical benefit (discontinuation despite clinical    benefit does not qualify), or-   3) History of intolerance to at least one biologic agent (including,    but not limited to infusion-related reaction, demyelination,    congestive heart failure (CHF), infection)

In one aspect, the patient is one who has previously been treated with,or is currently being treated with aminosalicylate, immunosuppressants,corticosteroids, and/or a biologic agent.

In one aspect, the Mayo Scoring System for Assessment of UlcerativeColitis Activity or any of the evaluations described hereinbefore or inthe Examples herein below is/are used to assess the efficacy ofupadacitinib in the treatment of ulcerative colitis, for examplemoderately to severely active ulcerative colitis. In one embodiment, theevaluation used to assess the efficacy of upadacitinib in the treatmentof ulcerative colitis is selected from the group consisting of the FullMayo score, the Partial Mayo score, the Adapted Mayo score, the IBDQ,the WPAI:UC, the EQ-5D-5L, the SF-36, the FACIT-F, the UC-SQ, the PGIC,and combinations thereof.

In one embodiment, in the context of the present disclosure, thetreatment of a patient having ulcerative colitis, and/or the inductionof clinical remission of ulcerative colitis and/or the induction ofclinical response and/or endoscopic improvement and/or endoscopicremission in a patient comprises an induction phase and a maintenancephase. In the induction phase, one or more doses of the JAK1 inhibitor,for example referred to herein as induction doses, are administered tothe patient, for example, orally. In the maintenance phase, a first doseof the JAK1 inhibitor, for example referred to herein as the maintenancedose, is administered to the patient followed by at least one additionaldose of the JAK1 inhibitor, for example, also referred to herein as amaintenance dose. The maintenance doses are, for example, administeredorally. The JAK1 inhibitor may be, for example, upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. Examplesof induction phases and maintenance phases are described herein.

In one aspect, a certain therapeutic result is achieved by the patientduring or at the end of the induction phase, for example clinicalremission. In other embodiments, the therapeutic result achieved by thepatient during or at the end of the induction phase is selected from thegroup consisting of endoscopic subscore of 0 or 1 at week 8, endoscopicsubscore of 0 at week 8, fecal calprotectin below 150 mg/kg at week 8,IBDQ response (increase of IBDQ≥16 from baseline) at week 8, RBS≥1 orabsolute RBS≤1 at week 8, or RBS of 0 at week 8. In one aspect, thepatient achieves clinical remission during or by the end of theinduction phase. In one aspect, the patient achieves endoscopicremission during or by the end of the induction phase.

In one aspect, the patient achieves endoscopic improvement of ulcerativecolitis during or by the end of the induction phase. In one aspect, thepatient achieves clinical remission and endoscopic improvement ofulcerative colitis during or at the end of the induction phase.

In one embodiment, the induction phase lasts for up to 16 weeks (e.g.,for up to 16 weeks following initiation of administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof). Thus, in one embodiment, the induction phase is 16 weeks. Inanother embodiment, the induction phase optionally lasts for less than16 weeks, for instance, for 2 weeks, for 3 weeks, for 4 weeks, for 5weeks, for 6 weeks, for 7 weeks, for 8 weeks, for 9 weeks, for 10 weeks,for 11 weeks, for 12 weeks, for 13 weeks, for 14 weeks, or for 15 weeks.In one aspect, the patient achieves an endoscopic remission within 8weeks, or within 12 weeks, or within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one aspect, the patient achieves a clinicalremission within 8 weeks, or within 12 weeks, or within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one aspect, the patientachieves an endoscopic improvement within 8 weeks, or within 12 weeks,or within 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneaspect, the patient achieves a clinical response within 8 weeks, orwithin 12 weeks, or within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one aspect, the patient achieves a clinical remission within8 weeks, or within 12 weeks, or within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, the patient achieves clinical remission within 2weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves clinical remission within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one embodiment, the patient achieves clinical response within 2 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, thepatient achieves clinical response within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof.

In one embodiment, the patient achieves endoscopic improvement orendoscopic remission within 2 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the patient achieves endoscopic improvementor endoscopic remission within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the patient achieves endoscopic improvementor endoscopic remission within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the patient achieves endoscopic improvementor endoscopic remission within 16 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, the patient achieves corticosteroid-free remissionwithin 12 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves corticosteroid-free remission within 8weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the corticosteroid-free remission is a clinical remission.In one embodiment, the corticosteroid-free remission is endoscopicremission.

In some embodiments, during or by the end of the induction phase (e.g.,lasting for up to 16 weeks, including for 2 weeks, 4 weeks, 6 weeks, 8weeks, 10 weeks, 12 weeks or for 16 weeks), the patient achieves atleast one therapeutic result selected from the group consisting of:

-   1) endoscopic improvement (defined as endoscopic subscore ≤1 within    8 weeks of initiating administration of upadacitinib or a    pharmaceutically acceptable salt or solid state form thereof,-   2) a Full Mayo score ≤2 with no subscore >1 within 8 weeks of    initiating administration of upadacitinib or a pharmaceutically    acceptable salt or solid state form thereof,-   3) clinical response (defined as decrease from baseline in the    Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease    in rectal bleeding subscore (RBS)≥1 or an absolute RBS of 0 or 1)    within 8 weeks of initiating administration of upadacitinib or a    pharmaceutically acceptable salt or solid state form thereof,-   4) clinical response within 2 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   5) change in Full Mayo score from Baseline to Week 8 after    initiating administration of upadacitinib or a pharmaceutically    acceptable salt or solid state form thereof,-   6) endoscopic remission (defined as endoscopic subscore of 0) within    8 weeks of initiating administration of upadacitinib or a    pharmaceutically acceptable salt or solid state form thereof,-   7) histologic improvement (defined as a decrease from baseline in    Geboes score) within 8 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   8) decrease in RBS≥1 or an absolute RBS≤1 within 8 weeks of    initiating administration of upadacitinib or a pharmaceutically    acceptable salt or solid state form thereof,-   9) RBS of 0 within 8 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   10) endoscopic improvement (endoscopic subscore of 0 or 1) within 8    weeks of initiating administration of upadacitinib or a    pharmaceutically acceptable salt or solid state form thereof,-   11) stool frequency subscore ≤1 within 8 weeks of initiating    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof,-   12) maintenance of clinical remission at Week 52 following initial    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof in patients who achieved clinical    remission within 8 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   13) endoscopic improvement within 52 weeks of initiating    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof,-   14) a Full Mayo score ≤2 with no subscore >1 within 52 weeks of    initiating administration of upadacitinib or a pharmaceutically    acceptable salt or solid state form thereof,-   15) clinical remission within 52 weeks of initiating administration    of upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof in patients who discontinued corticosteroid use prior    to initiating administration of upadacitinib or a pharmaceutically    acceptable salt or solid state form thereof,-   16) subjects who are taking corticosteroids at Baseline and are    steroid-free at within 52 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   17) endoscopic improvement at Week 52 following initial    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof in patients who achieved clinical    remission within 8 weeks of initiating administration of    upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   18) clinical response within 44 weeks of initiating administration    of upadacitinib or a pharmaceutically acceptable salt or solid state    form thereof,-   19) endoscopic remission within 52 weeks of initiating    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof,-   20) histologic improvement within 52 weeks of initiating    administration of upadacitinib or a pharmaceutically acceptable salt    or solid state form thereof,-   21) clinical remission per Adapted Mayo score (defined as SFS≤1, RBS    of 0, and endoscopy subscore ≤1), and combinations thereof.

In some embodiments, the patient achieves a clinical remission within 16weeks or within 12 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof, andfurther achieves any combination of additional therapeutic resultsselected from the group consisting of therapeutic results 1), 2), 3),4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19)20), 21) and combinations thereof. In one such embodiment, the inductionphase is 16 weeks. In one embodiment, the additional therapeutic resultis achieved within 8 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof, andis selected from the group consisting of therapeutic results 1), 2), 3),4), 5), 6), 7), 8), 9), 10), 11) and combinations thereof.

In one embodiment, the induction phase is 8 weeks, and the patientachieves a clinical remission within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and further achieves any combination ofadditional therapeutic results selected from the group consisting oftherapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12),13), 14), 15), 16), 17), 18), 19) 20), 21) and combinations thereof. Inone embodiment, the additional therapeutic result is achieved within 8weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the additional therapeutic result is achieved within 8 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, and is selected from thegroup consisting of therapeutic results 1), 2), 3), 4), 5), 6), 7), 8),9), 10), 11) and combinations thereof.

In one embodiment, the induction phase is 4 weeks, and the patientachieves a clinical remission within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and further achieves any combination ofadditional therapeutic results selected from the group consisting oftherapeutic results 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12),13), 14), 15), 16), 17), 18), 19) 20), 21) and combinations thereof. Inone embodiment, the additional therapeutic result is achieved within 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the additional therapeutic result is achieved within 4 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, and is selected from thegroup consisting of endoscopic improvement, clinical remission, clinicalresponse, endoscopic remission, histologic improvement, and combinationsthereof.

In one embodiment, the patient achieves a clinical remission within 4weeks, within 8 weeks, within 12 weeks, or within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, and/or achieves an endoscopic improvementwithin 4 weeks, within 8 weeks, within 12 weeks or within 16 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, and further achieves anadditional therapeutic result selected from the group consisting of adecrease from baseline in Partial Mayo score ≥2 points and ≥30% frombaseline plus a decrease in RBS≥1 or an absolute RBS≤1 over time within16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; clinicalresponse per Partial Mayo score within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a decrease from baseline in Partial Mayo score≥2 points and ≥30% from baseline plus a decrease in RBS≥1 or an absoluteRBS≤1 over time within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a decrease from baseline in Partial Mayo score ≥2 points and≥30% from baseline plus a decrease in RBS≥1 or an absolute RBS≤1 overtime within 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a decreasefrom baseline in Partial Mayo score ≥2 points and ≥30% from baselineplus a decrease in RBS≥1 or an absolute RBS≤1 over time within 2 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic remissionwithin 16 weeks of initiating administration of pharmaceuticallyupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic remission within 12 weeks of initiatingadministration of upadacitinib, or an acceptable salt or solid stateform thereof; an endoscopic remission within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; an endoscopic remission within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a clinical response within16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a clinicalresponse within 12 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; aclinical response within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a clinical response within 4 weeks of initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof; a Full Mayo score ≤2 with no subscore >1 within 16 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a Full Mayo score ≤2 withno subscore >1 within 12 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a Full Mayo score ≤2 with no subscore >1 within 8 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a Full Mayo score ≤2 withno subscore >1 within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic improvement within 16 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; an endoscopic improvement within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic improvementwithin 8 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; anendoscopic improvement within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a decrease from baseline in Full Mayo score ≥3 points and >30%accompanied by a decrease in RBS of ≥1 or an absolute RBS of 0 or 1within 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a decreasefrom baseline in Full Mayo score ≥3 points and >30% accompanied by adecrease in RBS of ≥1 or an absolute RBS of 0 or 1 within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a decrease from baseline inFull Mayo score ≥3 points and ≥30% accompanied by a decrease in RBS of≥1 or an absolute RBS of 0 or 1 within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a decrease from baseline in Full Mayo score ≥3points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or 1 within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and combinations thereof. In one embodiment, the patientachieves a clinical remission within 12 weeks or within 16 weeks ofinitiating administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof, and/or achieves a clinicalremission per Adapted Mayo score (defined as SFS≤1, RBS or 0, andendoscopy subscore ≤1) within 12 weeks of initiation administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the patient achieves a clinical response perAdapted Mayo score (defined as decrease from BL in the Adapted Mayoscore ≥2 points and ≥30% from BL, plus a decrease in RBS≥1 or anabsolute RBS≤1 at week 12 or 16. In one such embodiment, the inductionphase is 16 weeks, and the additional therapeutic result is selectedfrom the group consisting of a decrease from baseline in Partial Mayoscore ≥2 points and ≥30% from baseline plus a decrease in RBS≥1 or anabsolute RBS≤1 over time within 16 weeks, within 12 weeks, within 8weeks, within 4 weeks or within 2 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic remission within 16 weeks, within 12 weeks,within 8 weeks, or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a clinical response within 16, within 12 weeks, within 8 weeks,or within 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; anendoscopic improvement within 16 weeks, within 12 weeks, within 8 weeks,or within 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a FullMayo score ≤2 with no subscore >1 within 16 weeks, within 12 weeks,within 8 weeks, or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a decrease from baseline in Full Mayo score ≥3 points and ≥30%accompanied by a decrease in RBS of ≥1 or an absolute RBS of 0 or 1within 16 weeks, within 12 weeks, within 8 weeks, or within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; and combinations thereof.In one such embodiment, the induction phase is 12 weeks, and theadditional therapeutic result is selected from the group consisting of adecrease from baseline in Partial Mayo score ≥2 points and ≥30% frombaseline plus a decrease in RBS≥1 or an absolute RBS≤1 over time within12 weeks, within 8 weeks, within 4 weeks, or within 2 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, an endoscopic remissionwithin 12 weeks, within 8 weeks, or within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a clinical response within 12 weeks, within 8weeks, or within 4 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; anendoscopic improvement within 12 weeks, within 8 weeks, or within 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; a FullMayo score ≤2 with no subscore >1 within 12 weeks, within 8 weeks, orwithin 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, a decreasefrom baseline in Full Mayo score ≥3 points and ≥30% accompanied by adecrease in RBS of ≥1 or an absolute RBS of 0 or 1 within 12 weeks,within 8 weeks, or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and combinations thereof. In one such embodiment, the inductionphase is 8 weeks, and the additional therapeutic result is selected fromthe group consisting of a decrease from baseline in Partial Mayo score≥2 points and ≥30% from baseline plus a decrease in RBS≥1 or an absoluteRBS≤1 over time within 48 weeks, 8 weeks, within 4 weeks, or within 2weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; anendoscopic remission within 8 weeks or within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a clinical response within 8 weeks or within 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; anendoscopic improvement within 8 weeks or within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a Full Mayo score ≤2 with no subscore >1within 8 weeks or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, a decrease from baseline in Full Mayo score ≥3 points and ≥30%accompanied by a decrease in RBS of ≥1 or an absolute RBS of 0 or 1within 8 weeks or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and combinations thereof.

In one embodiment, the patient achieves clinical remission within 16weeks, or within 12 weeks, or within 8 weeks, or within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one such embodiment, thepatient is one who was taking corticosteroids at baseline but whodiscontinued corticosteroid use during treatment with the JAK1inhibitor.

In one embodiment, the additional therapeutic result may be a Full Mayoscore ≤2 with no subscore >1 within 16 weeks, or within 12 weeks, orwithin 8 weeks, or within 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one such embodiment, the patient is one who was takingcorticosteroids at baseline but who discontinued corticosteroid useduring treatment with the JAK1 inhibitor. In another embodiment, theadditional therapeutic result may be selected from the group consistingof an endoscopic remission within 16 weeks, within 12 weeks, within 8weeks, or within 4 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; aclinical response within 16 weeks, or 12 weeks, or 8 weeks, or 4 weeksof initiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a decrease from baseline inPartial Mayo score ≥2 points and ≥30% from baseline, plus a decrease inRBS≥1 or an absolute RBS≤1 over time within 16 weeks, or 12 weeks, or 8weeks, or 4 weeks, or 2 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a decrease from baseline in Full Mayo score ≥3 points and ≥30%accompanied by a decrease in RBS of ≥1 or an absolute RBS of 0 or 1within 16 weeks, or 12 weeks, or 8 weeks, or 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; and an endoscopic improvement within 16 weeks,or 12 weeks, or 8 weeks, or 4 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; and combinations thereof. In one such embodiment, the patientis one who was taking corticosteroids at baseline but who discontinuedcorticosteroid use during treatment with the JAK1 inhibitor.

In one embodiment, the additional therapeutic result may be an AdaptedMayo score (defined as SFS≤1, RBS of 0, and endoscopy subscore ≤1) at 16weeks, or within 12 weeks, or within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one such embodiment, the patient is one whowas taking corticosteroids at baseline but who discontinuedcorticosteroid use during treatment with the JAK1 inhibitor. In anotherembodiment, the additional therapeutic result may be selected from thegroup consisting of an endoscopic remission within 16 weeks, within 12weeks, or within 8 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof; aclinical response within 16 weeks, or 12 weeks, or 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a decrease from baseline in Partial Mayo score≥2 points and ≥30% from baseline, plus a decrease in RBS≥1 or anabsolute RBS≤1 over time within 16 weeks, or 12 weeks, or 8 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; a decrease from baseline inFull Mayo score ≥3 points and ≥30% accompanied by a decrease in RBS of≥1 or an absolute RBS of 0 or 1 within 16 weeks, or 12 weeks, or 8weeks, or 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, and anendoscopic improvement within 16 weeks, or 12 weeks, or 8 weeks, or 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; andcombinations thereof. In one such embodiment, the patient is one who wastaking corticosteroids at baseline but who discontinued corticosteroiduse during treatment with the JAK1 inhibitor.

In one particular embodiment, the induction phase is 8 weeks, and thepatient achieves a clinical remission (SF subscore ≤1, RBS of 0 andendoscopic subscore ≤1) within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof and an endoscopic improvement (i.e., an endoscopic subscore ≤1)within 6 weeks or within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In another embodiment, the induction phase is 4 weeks, and thepatient achieves a clinical remission within 4 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof and an endoscopic improvement within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof.

In one particular embodiment, the induction phase is 8 weeks, and thepatient achieves a clinical remission within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof and further achieves a full Mayo score ≤2, withno subscore >1 within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic improvement (i.e., an endoscopic subscore ≤1)within 6 weeks or within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; or combinations thereof. In another embodiment, the inductionphase is 4 weeks, and the patient achieves a clinical remission within 4weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof and furtherachieves a full Mayo score ≤2, with no subscore >1 within 4 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; an endoscopic improvementwithin 4 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, orcombinations thereof.

In one embodiment, the patient is administered upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, for atleast 52 weeks. The administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, mayinclude an induction phase (e.g., an induction phase of up to 16 weeks),and additional weeks (e.g., 36 weeks or longer) of a maintenance phase(discussed hereinafter). In other embodiments, the administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, may include a shorter induction phase (e.g., up to 4 weeks, 6weeks, 8 weeks, 10 weeks, 12 weeks, etc.), and a longer maintenancephase (e.g., a 12 week induction phase and a 40 week or longermaintenance phase).

In one embodiment, the induction phase is 8 weeks and the maintenancephase is 44 weeks. In some such embodiments, the patient may achieve atleast one therapeutic result selected from the group consisting of:clinical remission within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; endoscopic remission within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; full Mayo score ≤2, with no subscore >1 within52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; clinicalresponse within 52 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof;endoscopic improvement within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; decrease from baseline in Partial Mayo score ≥2 points and ≥30%from baseline, plus a decrease in RBS≥1 or an absolute RBS≤1 over timewithin 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, a decreasefrom baseline in Full Mayo score ≥3 points and ≥30% accompanied by adecrease in RBS of ≥1 or an absolute RBS of 0 or 1 within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof; histologic improvementwithin 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, stoolfrequency subscore ≤1 within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; a RBS of 0 within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; an endoscopic subscore ≤1 within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof, a change in IBDQ score from baseline within 52weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, andcombinations thereof.

In some embodiment when the patient is administered upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, for atleast 52 weeks, the patient is one who was taking corticosteroids atbaseline but who discontinued corticosteroid use during treatment withthe JAK1 inhibitor, and the therapeutic result may be selected from thegroup consisting of clinical remission within 52 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof; a endoscopic remission within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, a Full Mayo score ≤2 withno subscore >1 within 52 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof; clinical response within 52 weeks of initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof; decrease from baseline in Partial Mayo score ≥2 points and≥30% from baseline, plus a decrease in RBS≥1 or an absolute RBS≤1 overtime within 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; decreasefrom baseline in Full Mayo score ≥3 points and ≥30% accompanied by adecrease in RBS of ≥1 or an absolute RBS of 0 or 1 within 52 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof an endoscopic improvementwithin 52 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof; andcombinations thereof.

In one embodiment, in a method of the present disclosure, a patient isevaluated during or at the end of the induction phase for a therapeuticresult selected from the group consisting of clinical remission, a FullMayo score ≤2 with no subscore >1, endoscopic improvement, endoscopicremission, clinical response, decrease from baseline in Full Mayo score≥3 points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or 1, a decrease from baseline in Partial Mayo score ≥2 pointsand ≥30% from baseline, plus a decrease in RBS≥1 or an absolute RBS≤1over time, SF sub score, rectal bleeding subscore, endoscopic subscore,histologic improvement, fecal calprotectin level, hs-CRP, IBDQ score,and combinations thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for clinical remission during or atthe end of the induction phase. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for endoscopic improvementduring or at the end of the induction phase. In one embodiment, in amethod of the present disclosure, a patient is evaluated for achievementof Full Mayo score ≤2 with no subscore >1 during or at the end of theinduction phase. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for endoscopic remission during or atthe end of the induction phase. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for clinical response duringor at the end of the induction phase. In one embodiment, in a method ofthe present disclosure, a patient is evaluated for decrease frombaseline in Partial Mayo score ≥2 points and ≥30% from baseline, plus adecrease in RBS≥1 or an absolute RBS≤1 over time during or at the end ofthe induction phase. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for change in Full Mayo score frombaseline during or at the end of the induction phase. In one embodiment,in a method of the present disclosure, a patient is evaluated forhistologic improvement during or at the end of the induction phase. Inone embodiment, the induction phase is 2 weeks. In one embodiment, theinduction phase is 8 weeks. In one embodiment, the induction phase is 12weeks.

In one embodiment, in a method of the present disclosure, a patient isevaluated during or at the end of the maintenance phase for atherapeutic result selected from the group consisting of endoscopicimprovement, achievement of Full Mayo score ≤2 with no subscore >1,discontinuation of corticosteroid use and clinical remission per AdaptedMayo score, maintenance of clinical remission among subjects whoachieved clinical remission during the induction phase, endoscopicimprovement among subjects who achieved clinical remission during theinduction phase, clinical response, endoscopic remission, histologicimprovement, and combinations thereof.

In one embodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by being corticosteroid-free for 44weeks after discontinuing corticosteroids. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving clinical remission 4 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievingclinical remission 8 weeks after initial administration of upadacitinibor a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by achieving clinical remission 12weeks after initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving Full Mayo score ≤2 with no subscore >1within 52 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by achieving clinical remissiondefined as stool frequency subscore ≤1, rectal bleeding subscore of 0,and endoscopic subscore ≤1 with absence of friability within 52 weeksafter initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving a SF subscore of 0, a RBS of 0, andendoscopic subscore of 0. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga decrease from baseline in Partial Mayo score ≥2 points and ≥30% frombaseline, plus a decrease in RBS≥1 or an absolute RBS≤1 over time within2 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by achieving a decrease from baselinein Partial Mayo score ≥2 points and ≥30% from baseline, plus a decreasein RBS≥1 or an absolute RBS≤1 over time within 4 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga decrease from baseline in Partial Mayo score ≥2 points and ≥30% frombaseline, plus a decrease in RBS≥1 or an absolute RBS≤1 over time within12 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by achieving clinical response or adecrease from baseline in Full Mayo score ≥3 points and ≥30% accompaniedby a decrease in RBS of ≥1 or an absolute RBS of 0 or 1. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by achieving a decrease from baselinein Partial Mayo score ≥2 points and ≥30% from baseline, plus a decreasein RBS≥1 or an absolute RBS≤1 over time within 2 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievingclinical response or a decrease from baseline in Full Mayo score ≥3points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or 1. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by achieving a decreasefrom baseline in Partial Mayo score ≥2 points and ≥30% from baseline,plus a decrease in RBS≥1 or an absolute RBS≤1 over time within 4 weeksafter initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving clinical response or a decrease frombaseline in Full Mayo score ≥3 points and ≥30% accompanied by a decreasein RBS of ≥1 or an absolute RBS of 0 or 1. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving a decrease from baseline in Partial Mayoscore ≥2 points and ≥30% from baseline, plus a decrease in RBS≥1 or anabsolute RBS≤1 over time within 12 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving stoolfrequency subscore ≤1 within 2 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving stoolfrequency subscore ≤1 within 4 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving stoolfrequency subscore ≤1 within 12 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving rectalbleeding subscore of 0 over time. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for a therapeutic result byachieving an endoscopic subscore of <1 within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievingan endoscopic improvement within 12 weeks after initial administrationof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by achieving fecalcalprotectin below 150 mg/kg within 4 weeks after initial administrationof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by achieving fecalcalprotectin below 150 mg/kg within 8 weeks after initial administrationof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by achieving fecalcalprotectin below 150 mg/kg within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievingan IBDQ response (increase of IBDQ≥16 from Baseline) within 2 weeksafter initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by achieving an IBDQ response (increase of IBDQ≥16from Baseline) within 8 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving an IBDQresponse (increase of IBDQ≥16 from Baseline) within 12 weeks afterinitial administration of upadacitinib or a pharmaceutically acceptablesalt or solid state form thereof. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for a therapeutic result byachieving a change from Baseline in hs-CRP within 2 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga change from Baseline in hs-CRP within 8 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga change from Baseline in hs-CRP within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga change in Baseline in fecal calprotectin within 8 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga change in Baseline in fecal calprotectin within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinga change in corticosteroid dose within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by changefrom Baseline in Adapted Mayo score, Full Mayo score, Partial Mayo scoreand/or Mayo subscores within 12 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by change form Baseline inUCEIS scores within 12 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by achieving histologicremission (defined as Geboes score <2) within 8 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by achievinghistologic remission (defined as Geboes score <2) within 12 weeks afterinitial administration of upadacitinib or a pharmaceutically acceptablesalt or solid state form thereof. In one embodiment, in a method of thepresent disclosure, a patient is evaluated for a therapeutic result bychange from Baseline in histologic score within 8 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by changefrom Baseline in histologic score within 8 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by changefrom Baseline in laboratory and nutritional parameters (e.g.,hemoglobin, hematocrit, albumin, total protein concentration, andweight) within 8 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change from Baseline in laboratoryand nutritional parameters (e.g., hemoglobin, hematocrit, albumin, totalprotein concentration, and weight) within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by change inBaseline in subject-reported stool frequency (absolute values) within 8weeks after initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by change in Baseline in subject-reported stoolfrequency (absolute values) within 12 weeks after initial administrationof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by change from Baselinein IBDQ score within 8 weeks after initial administration ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, in a method of the present disclosure, apatient is evaluated for a therapeutic result by change from Baseline inIBDQ score within 12 weeks after initial administration of upadacitinibor a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change from Baseline in EQ-5D-5Lscore within 8 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change from Baseline in EQ-5D-5Lscore within 12 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change from Baseline in WPAI:UCscores within 8 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change from Baseline in WPAI:UCscores within 12 weeks after initial administration of upadacitinib or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change in SF-36, PCT, MCScomponents and domain scores within 8 weeks after initial administrationof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, in a method of the present disclosure,a patient is evaluated for a therapeutic result by change in SF-36, PCT,MCS components and domain scores within 12 weeks after initialadministration of upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for a therapeutic result by change inPGIC score within 8 weeks after initial administration of upadacitinibor a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, in a method of the present disclosure, a patient isevaluated for a therapeutic result by change in PGIC score within 12weeks after initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by change from Baseline in FACIT-F score within 8weeks after initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by change from Baseline in FACIT-F score within 12weeks after initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by change from Baseline in UC-SQ score within 8 weeksafter initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, in amethod of the present disclosure, a patient is evaluated for atherapeutic result by change from Baseline in UC-SQ score within 8 weeksafter initial administration of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, thepatient is administered at least 14 doses, 28 doses, or at least 42doses, or at least 56 doses of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, during the induction phase.

In one aspect, a certain therapeutic result is maintained by the patientduring the maintenance phase. The maintenance phase may last for anindefinite period of time. In one embodiment, the maintenance phase isat least 36 weeks, including at least 37 weeks, at least 38 weeks, atleast 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks,at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46weeks, at least 47 weeks, or at least 48 weeks after the patientachieves clinical remission or clinical response after the patientachieves clinical remission or clinical response. In one embodiment, themaintenance phase is at least 40 additional weeks. In one embodiment,the maintenance phase is at least 44 additional weeks after the patientachieves clinical remission or clinical response. In one embodiment, thetherapeutic result maintained by the patient during the maintenancephase is selected from the group consisting of clinical remission, aFull Mayo score ≤2 with no subscore >1, endoscopic remission, clinicalresponse, a decrease from baseline in Partial Mayo score ≥2 points and≥30% from baseline plus a decrease in RBS≥1 or an absolute RBS≤1, adecrease from baseline in Full Mayo score ≥3 points and ≥30% accompaniedby a decrease in RBS of ≥1 or an absolute RBS of 0 or 1, endoscopicimprovement, and combinations thereof. In one embodiment, thetherapeutic result maintained by the patient during the maintenancephase is endoscopic remission. In one embodiment, the therapeutic resultmaintained by the patient during the maintenance phase is endoscopicresponse. In one embodiment, the therapeutic result maintained by thepatient during the maintenance phase is clinical remission. In oneembodiment, the therapeutic result maintained by the patient during themaintenance phase is corticosteroid-free remission.

In one embodiment, in a method of the present disclosure, a patient isevaluated for clinical remission during the maintenance phase. In oneembodiment, a patient is evaluated for endoscopic improvement during themaintenance phase. In one embodiment, a patient is evaluated forclinical remission a Full Mayo score ≤2 with no subscore >1 during themaintenance phase. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for endoscopic remission during themaintenance phase. In one embodiment, in a method of the presentdisclosure, a patient is evaluated for clinical response, or a decreasefrom baseline in Partial Mayo score ≥2 points and ≥30% from baselineplus a decrease in RBS≥1 or an absolute RBS≤1, or a decrease frombaseline in Full Mayo score ≥3 points and ≥30% accompanied by a decreasein RBS of ≥1 or an absolute RBS of 0 or 1 during the maintenance phase.

In one embodiment, the present disclosure provides a method for treatingan inflammatory disease, in one aspect for treating ulcerative colitis,comprising (a) administering to a patient a dose of a JAK1 inhibitor(e.g., upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof) at week 0 and once daily (QD) thereafter for 8 weeks,wherein the dose is 45 mg QD. In one embodiment, the method furthercomprises (b) administering to the patient additional doses once dailythereafter for at least 44 additional weeks, wherein the dose is 15 mgor 30 mg QD. In one embodiment the dose is administered orally.

In one embodiment, 8 weeks after initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, a patient is evaluated for clinical remission and/or for a FullMayo score ≤2 with no subscore >1. In one embodiment, 8 weeks afterinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, a patient is evaluated forclinical response and/or for a decrease from baseline in Partial Mayoscore ≥2 points and ≥30% from baseline plus a decrease in RBS≥1 or anabsolute RBS≤1, and/or for a decrease from baseline in Full Mayo score≥3 points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or land/or for endoscopic improvement and/or for endoscopicremission. In one embodiment, 6 weeks after initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, a patient is evaluated for clinical remission and/or a FullMayo score ≤2 with no subscore >1 and/or for endoscopic remission. Inone embodiment, 6 weeks after initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof, apatient is evaluated for a decrease from baseline in Full Mayo score ≥3points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or 1 and/or clinical response and/or a decrease from baselinein Partial Mayo score ≥2 points and ≥30% from baseline plus a decreasein RBS≥1 or an absolute RBS≤1, and/or for endoscopic improvement. In oneembodiment, 4 weeks after initiating administration of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof, apatient is evaluated for clinical remission and/or for a Full Mayo score≤2 with no subscore >1 and/or for endoscopic remission. In oneembodiment, 4 weeks after initiating administration of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof, apatient is evaluated for a decrease from baseline in Full Mayo score ≥3points and ≥30% accompanied by a decrease in RBS of ≥1 or an absoluteRBS of 0 or land/or for clinical response and/or for a decrease frombaseline in Partial Mayo score ≥2 points and ≥30% from baseline plus adecrease in RBS≥1 or an absolute RBS≤1, and/or for endoscopicimprovement. In one embodiment, 2 weeks after initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof, a patient is evaluated for clinical remission and/or for aFull Mayo score ≤2 with no subscore >1 and/or for endoscopic remission.In one embodiment, 2 weeks after initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, a patient is evaluated for a decrease from baseline in FullMayo score ≥3 points and ≥30% accompanied by a decrease in RBS of ≥1 oran absolute RBS of 0 or 1 and/or for clinical response and/or for adecrease from baseline in Partial Mayo score ≥2 points and ≥30% frombaseline plus a decrease in RBS≥1 or an absolute RBS≤1, and/or forendoscopic improvement.

In one embodiment, 48 weeks after initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, a patient is evaluated for clinical remission per Adapted Mayoscore (defined sa SFS≤1, RBS of 0, and endoscopy subscore ≤1), clinicalremission per Full Mayo score (defined as a Full Mayo score ≤2 with nosubscore >1), clinical remission per Partial mayo score (defined asPartial Mayo score ≤2 with no subscore >1) over time; clinical remissiondefined as stool frequency subscore ≤1, rRBS of 0 and endoscopicsubscore ≤1 with absence of friability and clinical response per Adaptedmayo score (defined as decrease from BL in the Adapted Mayo score ≥2points and ≥30% from BL, plus a decrease in RBS≥1).

In one embodiment, the present disclosure provides a method for treatingulcerative colitis, comprising (a) administering to a patient a dose ofa JAK1 inhibitor (e.g., upadacitinib or a pharmaceutically acceptablesalt or solid state form thereof) at week 0 and once daily thereaftervia an oral route, wherein the doses of the JAK1 inhibitor comprise 15mg, 30 mg, or 45 mg QD, or any combination thereof.

In one embodiment, the present disclosure provides a method for treatingulcerative colitis, comprising administering to a patient 15 mg to 45 mgof a JAK1 inhibitor. In one embodiment, the present disclosure providesa method for treating ulcerative colitis, comprising administering to apatient orally 15 mg of a JAK1 inhibitor QD. In one embodiment, thepresent disclosure provides a method for treating ulcerative colitis,comprising administering to a patient orally 30 mg of a JAK1 inhibitorQD. In one embodiment, the present disclosure provides a method fortreating ulcerative colitis, comprising administering to a patientorally 45 mg of a JAK1 inhibitor QD. In any such embodiments, the JAK1inhibitor may be upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof. In any such embodiment, the JAK1 inhibitor maybe in a once daily modified release formulation. In any such embodiment,the patient may have moderately to severely active ulcerative colitisprior to treatment.

In one embodiment, the administration of a JAK1 inhibitor according tothe present disclosure is further described in the Examples herein belowor in FIG. 13.

In one embodiment, the present disclosure provides a method for treatingulcerative colitis, said method comprising a) administering at least oneinduction dose of a JAK1 inhibitor (e.g., upadacitinib or apharmaceutically acceptable salt or solid state form thereof) to apatient, wherein said induction dose comprises 15 mg to 45 mg of the JAK1 inhibitor. In one aspect, the induction dose comprises 15 mg or 30 mgor 45 mg. In one aspect, the induction dose comprises 45 mg. In oneaspect, the induction dose is administered orally. In one aspect, theinduction dose is administered QD. In one aspect, the induction dose isadministered for 8 weeks. In one aspect the induction dose isadministered for 6 weeks. In one aspect the induction dose isadministered for 4 weeks. In one embodiment, the induction dose isadministered for up to 12 weeks, including for 2 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12weeks.

In one embodiment, the induction dose comprises 45 mg of the JAK1inhibitor administered QD.

In one embodiment, the induction dose comprises 30 mg of the JAK1inhibitor administered QD.

In one embodiment, the induction dose comprises 15 mg of the JAK1inhibitor administered QD.

In one embodiment, the JAK1 inhibitor is upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

In one embodiment, the induction dose is in a once daily modifiedrelease formulation.

In one embodiment, the method further comprises b) administering a firstmaintenance dose of a JAK1 inhibitor (e.g., upadacitinib, orpharmaceutically acceptable salt or solid state form thereof), to thepatient after the last induction dose is administered; and c)administering at least one additional maintenance dose to the patientonce daily thereafter.

In one embodiment, the first maintenance dose comprises 15 mg to 30 mgof the JAK1 inhibitor. In one aspect, the first maintenance dosecomprises 15 mg or 30 mg of the JAK1 inhibitor. In one aspect, the firstmaintenance dose is smaller than the induction dose. In one aspect, thefirst maintenance dose is administered QD. In one aspect the firstmaintenance dose is 15 mg. In one aspect the first maintenance dose is30 mg. In one aspect, the first maintenance dose is administered orally.In one aspect, the first maintenance dose is in a once daily modifiedrelease formulation.

In one aspect, the at least one additional maintenance dose comprises 15mg to 30 mg of the JAK 1 inhibitor. In one aspect, the at least oneadditional maintenance dose comprises 15 mg or 30 mg. In one aspect, theat least one additional maintenance dose is administered orally. In oneaspect, the at least one additional maintenance dose is administered QD.In one embodiment, the at least one additional maintenance dosecomprises 15 mg of the JAK1 inhibitor administered QD. In oneembodiment, the at least one additional maintenance dose comprises 30 mgof the JAK1 inhibitor administered QD. In one aspect, the at least oneadditional maintenance dose is in a once daily modified releaseformulation.

In any of the foregoing embodiments, the JAK1 inhibitor may beupadacitinib or a pharmaceutically acceptable salt or solid state formthereof.

In one aspect, in any of the foregoing embodiments, the patient is onewho had an inadequate response to or experienced a loss of response toor intolerance to conventional treatment (e.g., aminosalicylate,corticosteroids, immunosuppressants) or to a previous treatment with abiologic agent. In one aspect, in any of the foregoing embodiments, thepatient is one who had an inadequate response to, a loss of response to,or experienced intolerance to a previous treatment with an anti-TNFagent.

In one aspect, in any of the foregoing embodiments, the patient is onewho is naïve to previous treatment with an aminosalicylate, acorticosteroid, an immunosuppressant, a biologic agent or an anti-TNFagent.

In one aspect, in any of the foregoing embodiments, the patient is onewho had moderately to severely active ulcerative colitis prior totreatment or administration of the induction dose.

In one embodiment, the present disclosure further provides a method forinducing clinical remission of ulcerative colitis or a Full Mayo scoreof ≤2 with no subscore >1 in a patient, said method comprising a)administering to the patient at least one induction dose of a JAK1inhibitor as described above or herein (e.g., upadacitinib or apharmaceutically acceptable salt or solid state form thereof). In oneembodiment, the induction dose comprises 30 mg to 45 mg of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, an induction dose is administered at week 0 and oncedaily (QD) thereafter for up to 12 weeks (e.g., for 4 weeks, 5 weeks, 6weeks, 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12weeks), wherein the dose is 30 mg QD or 45 mg QD. In one embodiment, themethod further comprises maintaining clinical remission of ulcerativecolitis or a Full Mayo score of ≤2 with no subscore >1, said methodfurther comprising b) administering a first maintenance dose of saidJAK1 inhibitor to the patient after the last induction dose isadministered and c) administering at least one additional maintenancedose to the patient thereafter as described above or herein. In oneembodiment, the at least one additional maintenance dose is administeredonce daily. In one embodiment, the additional maintenance doses areadministered once daily for at least 36 additional weeks, including forat least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least43 weeks, at least 44 weeks, at least 56 weeks, at least 112 weeks, atleast 308 weeks, or at least 420 weeks. In one embodiment, theadditional maintenance doses are administered once daily for at least 44additional weeks. In one embodiment, the maintenance dose is 15 mg or 30mg QD. In one embodiment the induction and maintenance doses areadministered orally. In one embodiment, the patient has activeulcerative colitis with an Adapted Mayo score of 5 to 9 points andendoscopy subscore of 2 or 3 before administration of the firstinduction dose. In one embodiment, the patient has moderately toseverely active ulcerative colitis prior to administration of the firstinduction dose. In one embodiment, the patient has had an inadequateresponse to or experienced intolerance to conventional treatment (e.g.,aminosalicylates, corticosteroids, immunosuppressants) or to a previoustreatment with a biologic agent and/or an anti-TNF agent. In oneembodiment, the patient is naïve to previous treatment withaminosalicylates, a corticosteroid, an immunosuppressant, a biologicagent, and/or an anti-TNF agent. In one embodiment, the clinicalremission or Full Mayo score of ≤2 with no subscore >1 is achievedwithin 4 weeks or within 8 weeks of initiating administration ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, the clinical remission or a Full Mayo scoreof ≤2 with no subscore >1 is achieved within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the clinical remission orFull Mayo score of ≤2 with no subscore >1 is achieved within 10 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, theclinical remission or Full Mayo score of ≤2 with no subscore >1 isachieved within 8 weeks of initiating administration of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves a stool frequency subscore ≤1, RBS of 0and endoscopic subscore ≤1 before administration of the firstmaintenance dose. In one embodiment, the patient achieves a full Mayoscore of ≤2 with no subscore >1 before administration of the firstmaintenance dose. In one embodiment, the induction and maintenance dosesare in once-daily, modified release formulations.

In one embodiment, the present disclosure provides a method for inducingendoscopic remission of ulcerative colitis, the method comprising (a)administering to a patient at least one induction dose of a JAK1inhibitor (e.g., upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof), wherein the induction dose comprises 30 to 45mg of upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, an induction dose is administered atweek 0 and once daily (QD) thereafter for up to 12 weeks (e.g., for 4weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks,or 11 weeks, or 12 weeks), wherein the dose is 30 mg QD or 45 mg QD. Inone embodiment, the method further comprises maintaining endoscopicremission of ulcerative colitis, said method further comprising (b)administering to the patient a first maintenance dose of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof, afterthe last induction dose is administered, and (c) administering at leastone additional maintenance dose once daily thereafter as described aboveor herein. In one embodiment, the at least one additional maintenancedose is administered once daily. In one embodiment, the additionalmaintenance doses are administered once daily for at least 36 additionalweeks, including for at least 36 weeks, at least 37 weeks, at least 38weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least42 weeks, at least 43 weeks, at least 44 weeks, at least 56 weeks, atleast 112 weeks, at least 308 weeks, or at least 420 weeks. In oneembodiment, the additional maintenance doses are administered once dailyfor at least 44 additional weeks. In one embodiment, the maintenancedose is 15 mg or 30 mg QD. In one embodiment the induction andmaintenance doses are administered orally. In one embodiment, thepatient has active ulcerative colitis with an Adapted Mayo score of 5 to9 points and an endoscopy subscore of 2 or 3 before administration ofthe first induction dose. In one embodiment, the patient has moderatelyto severely active ulcerative colitis prior to administration of thefirst induction dose. In one embodiment, the patient has had aninadequate response to or experienced intolerance to conventionaltreatment (e.g., aminosalicylates, corticosteroids, immunosuppressants)or to a previous treatment with a biologic and/or an anti-TNF agent. Inone embodiment, the patient is naïve to previous treatment with anaminosalicylate, a corticosteroid, an immunosuppressant, an anti-TNFagent and/or a biologic agent. In one embodiment, the endoscopicremission is achieved within 4 weeks or within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the endoscopic remission isachieved within 12 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, the endoscopic remission is achieved within 10 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, theendoscopic remission is achieved within 8 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the patient achieves anendoscopic subscore of 0 before administration of the first maintenancedose. In one embodiment, the induction and maintenance doses are inonce-daily, modified release formulations.

In one embodiment, the present disclosure further provides a method forinducing clinical response or inducing a decrease from baseline in FullMayo score ≥3 points and ≥30% accompanied by a decrease in RBS of ≥1 oran absolute RBS or 0 or 1 or inducing a decrease from baseline inPartial Mayo score ≥2 points and ≥30%, accompanied by a decrease in RBSof ≥1 or an absolute rectal bleeding subscore of ≤1 in an ulcerativecolitis in a patient, said method comprising a) administering to thepatient at least one induction dose of a JAK1 inhibitor as describedabove or herein (e.g., upadacitinib or a pharmaceutically acceptablesalt or solid state form thereof). In one embodiment, the induction dosecomprises 30 mg to 45 mg of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, aninduction dose is administered at week 0 and once daily (QD) thereafterfor up to 8 weeks (e.g., for 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8weeks), wherein the dose is 30 mg QD or 45 mg QD. In one embodiment, themethod further comprises maintaining clinical response of ulcerativecolitis or maintaining a decrease from baseline in Full Mayo score ≥3points and ≥30%, accompanied by a decrease in RBS of ≥1 or an absoluteRBS or 0 or 1 or maintaining a decrease from baseline in Partial Mayoscore ≥2 points and ≥30%, accompanied by a decrease in RBS of ≥1 or anabsolute rectal bleeding subscore of ≤1, said method further comprisingb) administering a first maintenance dose of said JAK1 inhibitor to thepatient after the last induction dose is administered and c)administering at least one additional maintenance dose to the patientthereinafter as described above or herein. In one embodiment, the atleast one additional maintenance dose is administered once daily. In oneembodiment, the additional maintenance doses are administered once dailyfor at least 36 additional weeks, including for at least 36 weeks, atleast 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks,at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44weeks, at least 56 weeks, at least 112 weeks, at least 308 weeks, or atleast 420 weeks. In one embodiment, the additional maintenance doses areadministered once daily for at least 44 additional weeks. In oneembodiment, the maintenance dose is 15 mg or 30 mg QD. In one embodimentthe induction and maintenance doses are administered orally. In oneembodiment, the patient has active ulcerative colitis with an AdaptedMayo score of 5 to 9 points and an endoscopy subscore of 2 or 3 beforeadministration of the first induction dose. In one embodiment, thepatient has moderately to severely active ulcerative colitis prior toadministration of the first induction dose. In one embodiment, thepatient has had an inadequate response to or experienced intolerance toa conventional treatment (e.g., aminosalicylates, corticosteroids,immunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with aminosalicylates, a corticosteroid, animmunosuppressant, a biologic agent and/or an anti-TNF agent. In oneembodiment, the clinical response or the decrease from baseline in FullMayo score ≥3 points and ≥30%, accompanied by a decrease in RBS of ≥1 oran absolute RBS or 0 or 1 or the decrease from baseline in Partial Mayoscore ≥2 points and ≥30%, accompanied by a decrease in RBS of ≥1 or anabsolute rectal bleeding subscore of ≤1 is achieved within 4 weeks orwithin 8 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the clinical response or the decrease from baseline in FullMayo score ≥3 points and ≥30%, accompanied by a decrease in RBS of ≥1 oran absolute RBS or 0 or 1 is achieved within 12 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the clinical response orthe decrease from baseline in Full Mayo score ≥3 points and ≥30%,accompanied by a decrease in RBS of ≥1 or an absolute RBS or 0 or 1 orthe decrease from baseline in Partial Mayo score ≥2 points and ≥30%,accompanied by a decrease in RBS of ≥1 or an absolute rectal bleedingsubscore of ≤1 is achieved within 10 weeks of initiating administrationof upadacitinib, or a pharmaceutically acceptable salt or solid stateform thereof. In one embodiment, the clinical response, or the decreasefrom baseline in Full Mayo score ≥3 points and ≥30%, accompanied by adecrease in RBS of ≥1 or an absolute RBS or 0 or 1 or the decrease frombaseline in Partial Mayo score ≥2 points and ≥30%, accompanied by adecrease in RBS of ≥1 or an absolute rectal bleeding subscore of ≤1 isachieved within 8 weeks of initiating administration of upadacitinib, ora pharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the patient achieves a decrease from baseline in AdaptedMayo score ≥2 points and ≥30%, accompanied by a decrease in RBS of ≥1 oran absolute rectal bleeding subscore of 0 or 1 before administration ofthe first maintenance dose. In one embodiment, the patient achieves adecrease from baseline in Partial Mayo score ≥2 points and ≥30%,accompanied by a decrease in RBS of ≥1 or an absolute rectal bleedingsubscore of ≤1 before administration of the first maintenance dose. Inone embodiment, the patient achieves a decrease from baseline in FullMayo score ≥3 points and ≥30%, accompanied by a decrease in RBS frombaseline of ≥1 or an absolute rectal bleeding subscore of 0 or 1 beforeadministration of the first maintenance dose. In one embodiment, theinduction and maintenance doses are in once-daily, modified releaseformulations.

In one embodiment, the present disclosure further provides a method forinducing endoscopic improvement of ulcerative colitis in a patient, saidmethod comprising a) administering to the patient at least one inductiondose of a JAK1 inhibitor as described above or herein (e.g.,upadacitinib or a pharmaceutically acceptable salt or solid state formthereof). In one embodiment, the induction dose comprises 30 to 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In one embodiment, an induction dose is administered at week 0and once daily (QD) thereafter for up to 12 weeks (e.g., for 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12weeks) wherein the dose is 30 mg QD or 45 mg QD. In one embodiment, themethod further comprises maintaining endoscopic improvement ofulcerative colitis, said method further comprising b) administering afirst maintenance dose of said JAK1 inhibitor to the patient after thelast induction dose is administered and c) administering at least oneadditional maintenance dose to the patient thereinafter as describedabove or herein. In one embodiment, the at least one additionalmaintenance dose is administered once daily. In one embodiment, theadditional maintenance doses are administered once daily for at least 36additional weeks, including for at least 36 weeks, at least 37 weeks, atleast 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks,at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 56weeks, at least 112 weeks, at least 308 weeks, or at least 420 weeks. Inone embodiment, the additional maintenance doses are administered oncedaily for at least 44 additional weeks. In one embodiment, themaintenance dose is 15 mg or 30 mg QD. In one embodiment the inductionand maintenance doses are administered orally. In one embodiment, thepatient has active ulcerative colitis with an Adapted Mayo score of 5 to9 points and an endoscopy subscore of 2 or 3 before administration ofthe first induction dose. In one embodiment, the patient has moderatelyto severely active ulcerative colitis prior to administration of thefirst induction dose. In one embodiment, the patient has had aninadequate response to or experienced intolerance to a conventionaltreatment (e.g., aminosalicylate, corticosteroids, andimmunosuppressants) or to a previous treatment with a biologic agentand/or an anti-TNF agent. In one embodiment, the patient is naïve toprevious treatment with an aminosalicylate a corticosteroid, animmunosuppressant, a biologic agent and/or an anti-TNF agent. In oneembodiment, the endoscopic improvement is achieved within 8 weeks orwithin 16 weeks of initiating administration of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof. In oneembodiment, the endoscopic improvement is achieved within 12 weeks ofinitiating administration of upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof. In one embodiment, theendoscopic improvement is achieved within 10 weeks of initiatingadministration of upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the endoscopic improvementis achieved within 8 weeks of initiating administration of upadacitinib,or a pharmaceutically acceptable salt or solid state form thereof. Inone embodiment, the patient achieves an endoscopic subscore ≤1 beforeadministration of the first maintenance dose. In one embodiment, theinduction and maintenance doses are in once-daily, modified releaseformulations.

In one embodiment, the present disclosure further provides a method ofmaintaining clinical remission or a method of maintaining a Full Mayoscore ≤2 with no subscore >1 of ulcerative colitis in a patient, saidmethod comprising administering 15 mg or 30 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereof to thepatient. In one embodiment, the upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof is administered once dailyfor at least 36 weeks, including for at least 37 weeks, at least 38weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least42 weeks, at least 43 weeks, or at least 44 weeks. In one embodiment theupadacitinib or a pharmaceutically acceptable salt or solid state formthereof is administered orally. In one embodiment, the patient has hadan inadequate response to or experienced intolerance to a conventionaltreatment (e.g., aminosalicylates, corticosteroids, immunosuppressants)or to a previous treatment with a biologic agent and/or an anti-TNFagent. In one embodiment, the patient is naïve to previous treatmentwith aminosalicylates, a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt or solid state form thereof is a inonce-daily, modified release formulation.

In one embodiment, the present disclosure further provides a method ofmaintaining clinical response or a method of maintaining a decrease frombaseline in Full Mayo score ≥3 points and ≥30%, accompanied by adecrease in RBS of ≥1 or an absolute RBS or 0 or 1 or a method ofmaintaining a decrease from baseline in Partial Mayo score ≥2 points and≥30%, accompanied by a decrease in RBS of 1 or an absolute rectalbleeding subscore of ≤1 in a patient, said method comprisingadministering 15 mg or 30 mg of upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof to the patient. In oneembodiment, the upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof is administered once daily for at least 36weeks, including for at least 37 weeks, at least 38 weeks, at least 39weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, atleast 47 weeks, or at least 48 weeks. In one embodiment the upadacitinibor a pharmaceutically acceptable salt or solid state form thereof isadministered orally. In one embodiment, the patient has had aninadequate response to or experienced intolerance to a conventionaltreatment (e.g., aminosalicylates, corticosteroids, immunosuppressants)or to a previous treatment with a biologic agent and/or an anti-TNFagent. In one embodiment, the patient is naïve to previous treatmentwith aminosalicylates, a corticosteroid, an immunosuppressant, abiologic agent and/or an anti-TNF agent. In one embodiment, the patientis a refractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt or solid state form thereof is a inonce-daily, modified release formulation.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic improvement or endoscopic remission of ulcerativecolitis in a patient, said method comprising administering 15 mg or 30mg of upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof to the patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt or solid state form thereof isadministered once daily for at least 36 weeks, including for at least 37weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, atleast 45 weeks, at least 46 weeks, at least 47 weeks, or at least 48weeks. In one embodiment the upadacitinib or a pharmaceuticallyacceptable salt or solid state form thereof is administered orally. Inone embodiment, the patient has had an inadequate response to orexperienced intolerance to a conventional treatment (e.g.,aminosalicylates, corticosteroids, immunosuppressants) or to a previoustreatment with a biologic agent and/or an anti-TNF agent. In oneembodiment, the patient is naïve to previous treatment withaminosalicylates, a corticosteroid, an immunosuppressant, a biologicagent and/or an anti-TNF agent. In one embodiment, the patient is arefractory patient. In one embodiment, the upadacitinib or apharmaceutically acceptable salt or solid state form thereof is a inonce-daily, modified release formulation.

In one aspect, induction doses for the methods disclosed herein areadministered for 8 weeks in a dose regimen described in Table 12. In oneaspect, induction doses are administered for 8 weeks in a dose regimendescribed in Table 12. In one aspect, maintenance doses are administeredfor 44 weeks or more in a dose regimen described in Table 12. In oneaspect, induction doses for the methods disclosed herein areadministered for 8 weeks and the maintenance doses are administered for44 weeks in a dosing regimen as described in Table 12.

TABLE 12 Doses and Dosing Regimens (QD) Induction Frequency ofMaintenance Frequency of Dose (mg) induction doses dose (mg) maintenancedose 7.5 QD 7.5 QD 15 QD 15 QD 30 QD 15 QD 30 QD 30 QD 45 QD 15 QD 45 QD30 QD

In one particular embodiment, the induction dose is 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 30 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In another embodiment, the induction dose is 45 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 15 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In one embodiment, the induction dose is 30 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 30 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In one embodiment, the induction dose is 30 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD, and the maintenance dose, and any additionalmaintenance dose administered thereafter, is 15 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereofadministered QD. In one embodiment, the induction dose is 30 mg or 45 mgof upadacitinib or a pharmaceutically acceptable salt or solid stateform thereof administered QD, and the maintenance dose, and anyadditional maintenance dose administered thereafter, is 15 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD. In one embodiment, the induction dose is 30 mgor 45 mg of upadacitinib or a pharmaceutically acceptable salt or solidstate form thereof administered QD, and the maintenance dose, and anyadditional maintenance dose administered thereafter, is 7.5 mg ofupadacitinib or a pharmaceutically acceptable salt or solid state formthereof administered QD.

In one aspect, induction doses for the methods disclosed herein areadministered for 16 weeks in a dose regimen described in Table 13. Inone aspect, induction doses are administered for 16 weeks in a doseregimen described in Table 13. In one aspect, maintenance doses areadministered for 44 weeks or more in a dose regimen described in Table13. In one aspect, induction doses for the methods disclosed herein areadministered for 16 weeks and the maintenance doses are administered for36 weeks in a dosing regimen as described in Table 13.

TABLE 13 Doses and Dosing Regimens (QD) Induction Frequency ofMaintenance Frequency of Dose (mg) induction doses dose (mg) maintenancedose 45 QD 15 QD 45 QD 30 QD

In one embodiment, the present disclosure provides a method ofmaintaining clinical remission of ulcerative colitis in a patient, saidmethod comprising administering to the patient a daily maintenance doseof upadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid daily maintenance dose is administered orally once a day andcomprises 30 mg of upadacitinib, or a 30 mg free base equivalent amountof the pharmaceutically acceptable salt thereof; wherein said patientmaintains clinical remission.

In one embodiment, the present disclosure provides a method ofmaintaining endoscopic improvement of ulcerative colitis in a patient,said method comprising administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 30 mg of upadacitinib, or a 30 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic improvement.

In one embodiment, the present disclosure provides a method ofmaintaining endoscopic remission of ulcerative colitis in a patient,said method comprising administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 30 mg of upadacitinib, or a 30 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic remission.

In one embodiment, the present disclosure provides a method ofmaintaining clinical remission of ulcerative colitis in a patient, saidmethod comprising administering to the patient a daily maintenance doseof upadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid daily maintenance dose is administered orally once a day andcomprises 15 mg of upadacitinib, or a 15 mg free base equivalent amountof the pharmaceutically acceptable salt thereof; wherein said patientmaintains clinical remission.

In one embodiment, the present disclosure provides a method ofmaintaining endoscopic improvement of ulcerative colitis in a patient,said method comprising administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 15 mg of upadacitinib, or a 15 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic improvement.

In one embodiment, the present disclosure provides a method ofmaintaining endoscopic remission of ulcerative colitis in a patient,said method comprising administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 15 mg of upadacitinib, or a 15 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic remission.

In one embodiment of the method of maintaining clinical remission,endoscopic improvement, or endoscopic remission of ulcerative colitis,the patient has moderately to severely active ulcerative colitis.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In one embodiment, the clinical remission, endoscopic improvement orendoscopic remission is maintained for at least 52 weeks.

In one embodiment, the patient demonstrated an inadequate response to,loss of response to or intolerance to one or more corticosteroids,immunosuppressants, or biologic therapies.

In one embodiment, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.In one embodiment, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In one embodiment, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week. In oneembodiment, the patient is unable to taper corticosteroid below a doseequivalent to prednisone 10 mg daily orally without recurrent activedisease.

In one embodiment, the intolerance of said patient to corticocosteroidsleads to Cushing's syndrome, osteopenia, osteoporosis, hyperglycemia,insominia or infection. In one embodiment, the patient experiencingintolerance to immunosuppressants experienced nausea, vomiting,abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia orinfection.

In one embodiment, the patient experiencing the inadequate response toimmunosuppressants experienced signs and symptoms of persistently activedisease despite a history of at least one 90-day regimen of oralazathioprine, 6-mercaptopurine, injectable methotrexate or tacrolimus.In one embodiment, the patient experiencing the inadequate response tobiologic therapies experienced signs and symptoms of persistently activedisease despite a history of at least one 6-week induction regimen ofinfliximab comprising a greater than or equal to 5 mg/kg intravenousdose at 0, 2 and 6 weeks; at least one 4-week induction regimen ofadalimumab comprising one 160 mg subcutaneous dose followed by one 80 mgsubcutaneous dose or one 80 mg subcutaneous dose, followed by one 40 mgsubcutaneous dose at least two weeks apart; at least one 2-weekinduction regimen of golimumab comprising one 200 mg subcutaneous dosefollowed by one 100 mg subcutaneous dose at least 2 weeks apart; or atleast one 6-week induction regimen of vedolizumab comprising a 300 mgintravenous dose at 0, 2 and 6 weeks.

In one embodiment, the patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit. In one embodiment,the patient experiencing intolerance to biologic therapies experiencedinfusion-related reaction, demyelination, congestive heart failure ofinfection.

In one embodiment, the clinical remission achieved is defined by anAdapted Mayo score ≤2. In one embodiment, the clinical remissioncomprises an SFS≤1 and not greater than baseline, a RBS of 0, and anendoscopic subscore ≤1.

In one embodiment, the clinical remission is defined by an Adapted Mayoscore ≤2, and is corticosteroid free. In one embodiment, the patient inclinical remission has been corticosteroid free for 90 days or moreimmediately preceding week 52 of daily maintenance dose administration.For example, in some embodiments, the patient discontinuedcorticosteroid use at least 90 days prior to the end of a 52 week periodof administration of the maintenance dose.

In one embodiment, the patient exhibits a Histologic Endoscopic MucosalImprovement (HEMI) comprising an endoscopic score ≤1 and a Geboes score≤3.1 at week 52 (i.e., following 52 weeks of daily maintenance doseadministration),

In one embodiment, the patient exhibits mucosal healing comprising anendoscopic score of 0 and a Geboes score <2 at week 52 (i.e., following52 weeks of daily maintenance dose administration),

In one embodiment, the patient does not exhibit bowel urgency during themaintenance period. In one embodiment, the patient does not exhibitbowel urgency at week 52 (i.e., following 52 weeks of daily maintenancedose administration),

In one embodiment, the patient does not exhibit abdominal pain duringthe maintenance period. In one embodiment, the patient does not exhibitabdominal pain at week 52 (i.e., following 52 weeks of daily maintenancedose administration).

In one embodiment, the present disclosure further provides a method ofinducing clinical remission of ulcerative colitis in a patient, saidmethod comprising: (a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for up to 16 weeksand comprises 45 mg of upadacitinib, or a 45 mg free base equivalentamount of a pharmaceutically acceptable salt thereof; and (b) whereinsaid patient achieves clinical remission within 16 weeks ofadministration of the first induction dose.

In one embodiment, the present disclosure further provides a method ofinducing clinical remission of ulcerative colitis in a patient, saidmethod comprising: (a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day and comprises 45mg of upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and (b) continuing theadministering until said patient achieves clinical remission.

In one embodiment, the clinical remission is defined by an Adapted Mayoscore ≤2.

In one embodiment, the method comprises an SFS≤1 and not greater thanbaseline, a RBS of 0, and an endoscopic subscore ≤1.

In one embodiment, the clinical remission is achieved after more than 8weeks, but within 16 weeks of administration of the first 45 mginduction dose.

In one embodiment, the present disclosure further provides a method ofinducing inducing clinical remission of ulcerative colitis, said methodcomprising: (a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and (b)wherein the patient achieves clinical response within 8 weeks ofadministration of the first 45 mg induction dose, wherein the patientwas previously treated with 45 mg of upadacitinib for at least 8 weeksand did not exhibit a clinical response.

In one embodiment, the present disclosure further provides a method ofinducing clinical response in a patient having ulcerative colitis, saidmethod comprising: (a) administering to the patient an induction dose ofupadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid induction dose is administered orally once a day for at least 8weeks and comprises 45 mg of upadacitinib, or a 45 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; and (b)wherein the patient achieves clinical response within 8 weeks ofadministration of the first 45 mg induction dose, wherein the patientwas previously treated with 45 mg of upadacitinib for at least 8 weeksand did not exhibit a clinical response.

In one embodiment, the present disclosure further provides a method ofinducing a clinical response in a patient with moderately to severelyactive ulcerative colitis, said method comprising: a) administering tothe patient at least one induction dose of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, whereinsaid induction dose comprises 45 mg of upadacitinib, or apharmaceutically acceptable salt or solid state form thereof.

In one such embodiment, the clinical response is a clinical response iswherein the patient has a decrease from a baseline Adapted Mayo scoregreater than or equal to 2 points and greater than or equal to 30%accompanied by a decrease in rectal bleeding subscore of greater than orequal to 1 or an absolute rectal bleeding subscore of 0 or 1. In anothersuch embodiment, the clinical response is a clinical response is whereinthe patient has a decrease from a baseline Full Mayo score greater thanor equal to 3 points and greater than or equal to 30% accompanied by adecrease in rectal bleeding subscore from baseline of greater than orequal to 1 or an absolute rectal bleeding subscore of 0 or 1.

In yet another embodiment, the method further comprises maintaining theclinical response, said method further comprising: b) administering afirst maintenance dose of upadacitinib, or a pharmaceutically acceptablesalt or solid state form thereof to the patient after the last inductiondose is administered; and c) administering at least one additionalmaintenance dose once daily thereafter.

In another embodiment, the induction dose comprises 45 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof. In another embodiment, the first maintenance dose and/or the atleast one additional maintenance dose comprises 15 mg to 30 mg ofupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof.

In one embodiment, the present disclosure further provides a method ofmaintaining clinical remission of ulcerative colitis in a patient, saidmethod comprising: administering to the patient a daily maintenance doseof upadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid daily maintenance dose is administered orally once a day andcomprises 30 mg of upadacitinib, or a 30 mg free base equivalent amountof the pharmaceutically acceptable salt thereof; wherein said patientmaintains clinical remission.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic improvement of ulcerative colitis in a patient,said method comprising: administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 30 mg of upadacitinib, or a 30 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic improvement.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic remission of ulcerative colitis in a patient,said method comprising: administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 30 mg of upadacitinib, or a 30 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic remission.

In one embodiment, the present disclosure further provides a method ofmaintaining clinical remission of ulcerative colitis in a patient, saidmethod comprising: administering to the patient a daily maintenance doseof upadacitinib, or a pharmaceutically acceptable salt thereof, whereinsaid daily maintenance dose is administered orally once a day andcomprises 15 mg of upadacitinib, or a 15 mg free base equivalent amountof the pharmaceutically acceptable salt thereof; wherein said patientmaintains clinical remission.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic improvement of ulcerative colitis in a patient,said method comprising: administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 15 mg of upadacitinib, or a 15 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic improvement.

In one embodiment, the present disclosure further provides a method ofmaintaining endoscopic remission of ulcerative colitis in a patient,said method comprising: administering to the patient a daily maintenancedose of upadacitinib, or a pharmaceutically acceptable salt thereof,wherein said daily maintenance dose is administered orally once a dayand comprises 15 mg of upadacitinib, or a 15 mg free base equivalentamount of the pharmaceutically acceptable salt thereof; wherein saidpatient maintains endoscopic remission.

In some embodiments, said patient has moderately to severely activeulcerative colitis.

In some embodiments, the clinical remission, endoscopic improvement orendoscopic remission is corticosteroid free.

In some embodiments, the clinical remission, endoscopic improvement orendoscopic remission is maintained for at least 52 weeks.

In some embodiments, said patient demonstrated an inadequate responseto, loss of response to or intolerance to one or more corticosteroids,immunosuppressants, or biologic therapies.

In some embodiments, the immunosuppressants are selected form oralazathioprine, 6-mercaptopurine, injectable methotrexate and tacrolimus.

In some embodiments, the biologic therapy is selected from infliximab,adalimumab, golimumab and vedolizumab.

In some embodiments, the inadequate response in said patient takingcorticosteroids is defined as said patient experiencing signs andsymptoms of persistently active disease despite a history of at leastone induction regimen that included a dose equivalent to prednisone ≥40mg/day orally for 3 to 4 weeks or intravenously for one week.

In some embodiments, the said patient is unable to taper corticosteroidbelow a dose equivalent to prednisone 10 mg daily orally withoutrecurrent active disease.

In some embodiments, the intolerance of said patient tocorticocosteroids leads to Cushing's syndrome, osteopenia, osteoporosis,hyperglycemia, insominia or infection.

In some embodiments, the said patient experiencing the inadequateresponse to immunosuppressants experienced signs and symptoms ofpersistently active disease despite a history of at least one 90-dayregimen of oral azathioprine, 6-mercaptopurine, injectable methotrexateor tacrolimus.

In some embodiments, said patient experiencing intolerance toimmunosuppressants experienced nausea, vomiting, abdominal pain,pancreatitis, liver enzyme abnormalities, lymphopenia or infection.

In some embodiments, said patient experiencing the inadequate responseto biologic therapies experienced signs and symptoms of persistentlyactive disease despite a history of: at least one 6-week inductionregimen of infliximab comprising a greater than or equal to 5 mg/kgintravenous dose at 0, 2 and 6 weeks; at least one 4-week inductionregimen of adalimumab comprising one 160 mg subcutaneous dose followedby one 80 mg subcutaneous dose or one 80 mg subcutaneous dose, followedby one 40 mg subcutaneous dose at least two weeks apart; at least one2-week induction regimen of golimumab comprising one 200 mg subcutaneousdose followed by one 100 mg subcutaneous dose at least 2 weeks apart; orat least one 6-week induction regimen of vedolizumab comprising a 300 mgintravenous dose at 0, 2 and 6 weeks.

In some embodiments, said patient experiencing inadequate response tobiologic therapies experienced recurrence of symptoms during scheduledmaintenance dosing following prior clinical benefit.

In some embodiments, said patient experiencing intolerance to biologictherapies experienced infusion-related reaction, demyelination,congestive heart failure of infection.

In some embodiments, the clinical remission is defined by an AdaptedMayo score ≤2.

In some embodiments, the method comprises an SFS≤1 and not greater thanbaseline, a RBS of 0, and an endoscopic subscore ≤1.

In some embodiments, the clinical remission is defined by an AdaptedMayo score ≤2, and is corticosteroid free.

In some embodiments, the patient has been corticosteroid free for 90days or more immediately preceding week 52 of daily maintenance doseadministration.

In some embodiments, the patient exhibits a Histologic EndoscopicMucosal Improvement (HEMI) comprising an endoscopic score ≤1 and aGeboes score ≤3.1 at week 52.

In some embodiments, the patient exhibits mucosal healing comprising anendoscopic score of 0 and a Geboes score <2 at week 52.

In some embodiments, the patient does not exhibit bowel urgency at week52.

In some embodiments, the patient does not exhibit abdominal pain at week52.

In one embodiment, the present disclosure further provides a method ofinducing Histologic Endoscopic Mucosal Improvement (HEMI) in a patientwith ulcerative colitis, said method comprising: administering to thepatient an induction dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said induction dose is administeredorally once a day for at least 8 weeks and comprises 45 mg ofupadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; and wherein said patientachieves Histologic Endoscopic Mucosal Improvement (HEMI) comprising anendoscopic score ≤1 and a Geboes score ≤3.1 within 8 weeks ofadministration of the induction dose.

In one embodiment, the present disclosure further provides a method ofinducing and maintaining Histologic Endoscopic Mucosal Improvement(HEMI) in a patient with ulcerative colitis, said method comprising:administering to the patient an induction dose of upadacitinib, or apharmaceutically acceptable salt thereof, wherein said induction dose isadministered orally once a day for at least 8 weeks and comprises 45 mgof upadacitinib, or a 45 mg free base equivalent amount of apharmaceutically acceptable salt thereof; wherein said patient achievesHistologic Endoscopic Mucosal Improvement (HEMI) comprising anendoscopic score ≤1 and a Geboes score ≤3.1 within 8 weeks ofadministration of the first induction dose; administering to the patienta maintenance dose of upadacitinib, or a pharmaceutically acceptablesalt thereof, wherein said first maintenance dose is administered orallyonce a day for at least 52 weeks and comprises 15 mg of upadacitinib or30 mg of upadacitinib, or a 15 mg or 30 mg free base equivalent amountof a pharmaceutically acceptable salt thereof after the last inductiondose is administered; wherein said patient maintains HistologicEndoscopic Mucosal Improvement (HEMI) comprising an endoscopic score ≤1and a Geboes score ≤3.1 for 52 weeks after administration of the firstmaintenance dose.

In one embodiment, the present disclosure further provides a method ofmaintaining Histologic Endoscopic Mucosal Improvement (HEMI) in apatient with ulcerative colitis, said method comprising: administeringto the patient a maintenance dose of upadacitinib, or a pharmaceuticallyacceptable salt thereof, wherein said first maintenance dose isadministered orally once a day for at least 52 weeks and comprises 15 mgof upadacitinib or 30 mg of upadacitinib, or a 15 mg or 30 mg free baseequivalent amount of a pharmaceutically acceptable salt thereof; whereinsaid patient maintains Histologic Endoscopic Mucosal Improvement (HEMI)comprising an endoscopic score ≤1 and a Geboes score ≤3.1 for 52 weeksafter administration of the first maintenance dose.

V. Preparation of Upadacitinib

The synthesis of the compounds of the disclosure, including(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(upadacitinib) and pharmaceutically acceptable salts thereof is providedin U.S. Pat. No. 8,426,411, the entire content of which is incorporatedherein by reference. In one embodiment, upadacitinib, andpharmaceutically acceptable salts thereof, may be synthesized accordingto the methods described in U.S. patent application Ser. No. 15/295,561,which is herein incorporated by referenced. For example, upadacitinibmay be synthesized using synthetic transformations such as thoseillustrated in Schemes I-IIIa. Starting materials are commerciallyavailable, may be prepared by the procedures described in U.S. patentapplication Ser. No. 15/295,561, by literature procedures, or byprocedures that would be well known to one skilled in the art of organicchemistry (see, for example, Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 2^(nd)edition”, 1999, Wiley-VCH or Greene, T. W. and Wuts, P. G. M.“Protective Groups in Organic Synthesis, 3^(rd) Edition”, 1999,Wiley-Interscience).

A process for preparing upadacitinib is illustrated in Scheme I.Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I)or a pharmaceutically acceptable salt thereof with trimethylsulfoxoniumchloride gives sulfur ylide (II). Contacting sulfur ylide (II) with LiXand a sulfonic acid yields the corresponding halomethyl ketone (III).Reaction of (III) with (IV) in the presence of a base yields (V).Cyclization of (V) in the presence of a perfluoro acid anhydride and anorganic base produces (VI). Removal of the protecting group andcontacting the deprotected compound with an acid yields apharmaceutically acceptable salt of (VII). Reacting the pharmaceuticallyacceptable salt of (VII) with 2,2,2-trifluoroethylamine producesupadacitinib.

wherein:

PG is a protecting group;

X is Br or Cl;

R₁ is selected from the group consisting of alkyl, aryl, and —OR₂;

R₂ is alkyl; and

Ts is tosyl.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In another embodiment, theprotecting group is carboxybenzyl.

In another embodiment, R₁ is —OR₂, and R₂ is methyl or ethyl. In suchembodiments, the compound of formula (IV) is a compound of formula(IVa):

wherein R₂ is methyl or ethyl.

In certain embodiments, a pharmaceutically acceptable salt of a compoundof the compound of formula (I) is used in the reaction of step (a). Inone embodiment, the pharmaceutically acceptable salt of the compound offormula (I) is selected from the group consisting of thenaphthalenethane amine salt (Ia) and the dicyclohexylamine salt (Ib)

wherein Cbz is carboxybenzyl.

In one embodiment, the pharmaceutically acceptable salt of compound(VII) is selected from the group consisting of (VIIa), (VIIb), and(VIIc)

Another process for preparing upadacitinib is illustrated in Scheme Ia.Reaction of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylatedicyclohexylamine salt (Ib) with trimethylsulfoxonium chloride in thepresence of carbonyldiimidazole and a strong base gives sulfur ylide(IIa). Contacting sulfur ylide (IIa) with lithium bromide and a sulfonicacid yields the corresponding bromomethyl ketone (IIIa). Reaction of(IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa)in the presence of lithium tert-butoxide yields (Va). Cyclization of(Va) in the presence of a perfluoro acid anhydride and an organic baseproduces (VIa). Removal of the carboxybenzyl protecting group andcontacting the deprotected compound with hydrochloric acid yields thepharmaceutically acceptable salt (VIIa). Reacting the pharmaceuticallyacceptable salt (VIIa) with 2,2,2-trifluoroethylamine producesupadacitinib.

wherein:

Cbz is carboxybenzyl;

Ts is tosyl; and

R₂ is methyl or ethyl.

The reaction in step (a) of Schemes I and Ia is generally accomplishedin the presence of a coupling agent, such as carbonyldiimidazole (CDI),and a strong base. The strong base may be, for example, potassiumtert-butoxide, sodium tert-butoxide, or combinations thereof. The step(a) reaction may be conducted in any suitable solvent including, but notlimited to, tetrahydrofuran, water, and methyl tert-butyl ether. In oneembodiment, the reaction is conducted in the presence ofcarbonyldiimidazole and potassium tert-butoxide.

More particularly, in certain embodiments, a solution of a compound offormula (I), (Ia), or (Ib) in solvent is slowly added (e.g., over 30minutes) to a slurry of CDI in solvent, and the resulting mixture isstirred at room temperature for 30 minutes to 12 hours, and typicallyfor about 1 hour. The resulting solution is slowly added (e.g., over 15minutes) to a suspension of the trimethylsulfoxonium chloride, strongbase, and solvent, while maintaining the internal temperature below −1°C. In another embodiment, the reaction is quenched and the resultingcompound of formula (II) or (IIa) is isolated prior to step (b).

In some embodiments, the reaction of step (a) may further involvecontact of (Ia) or (Ib) with an acid prior to reaction with thetrimethylsulfoxonium chloride, in order to extract the amine to obtain acompound of formula (I). Suitable acids include any mineral acid ororganic acid, such as phosphoric acid, hydrochloric acid (HCl), aceticacid (HOAc), citric acid, and the like. The compound of formula (I) maysubsequently be taken up in a suitable solvent, and reacted withtrimethylsulfoxonium chloride, as described herein. In one embodiment, apharmaceutically acceptable salt of a compound of formula (I) is used instep (a), wherein the pharmaceutically acceptable salt is (Ia) or (Ib).

In step (b) of Schemes I and Ia, a compound of formula (II) or (IIa) iscontacted with LiX and a sulfonic acid to form a compound of formula(III) or (IIIa), respectively. In one embodiment, the sulfonic acid isselected from the group consisting of methanesulfonic acid andp-toluenesulfonic acid. In one embodiment, the sulfonic acid isp-toluenesulfonic acid. LiX may be selected from lithium bromide andlithium chloride. In one embodiment, LiX is lithium bromide. In oneembodiment, the reaction is conducted in lithium bromide andp-toluensulfonic acid. The reaction of step (b) may be conducted in anysuitable solvent including, but not limited to tetrahydrofuran, ethylacetate, heptanes, ethanol, water, and combinations thereof.

More particularly, in certain embodiments, the sulfonic acid is added toa solution of the compound of formula (II) or (IIa) and LiX in asolvent. The resulting mixture is warmed to about 35° C. to about 65° C.and stirred overnight. In one embodiment, the mixture is warmed to about40° C. and stirred overnight. The mixture is cooled to room temperatureand washed. The compound of formula (III) or (IIIa) may be isolated, oroptionally used in the next step without purification.

In step (c) of Schemes I and Ia a compound of formula (III) or (IIIa)are reacted with a compound of formula (IV) or (IVa) (prepared asdescribed herein). The step (c) reaction is conducted in the presence ofa base, such as lithium tert-butoxide, sodium tert-butoxide, orcombinations thereof. In one embodiment, the base is lithiumtert-butoxide. The reaction of step (c) may be conducted in any suitablesolvent including, but not limited to dimethylacetamide,tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, andcombinations thereof.

More particularly, in certain embodiments, the base is added to a cooledsuspension of the compound of formula (III) or (IIIa) in a solvent. Theresulting solution is stirred for about 30 minutes to about 12 hours, orabout 30 minutes, and cooled to about −20° C. to about 0°, or about −10°C. In one embodiment, the solution is stirred for about 30 minutes andcooled to about −20° C. to about 0°. A solution of a compound of formula(IV) or (IVa) in a solvent is slowly added (e.g., over 30 minutes), andthe resulting mixture is stirred for about 30 minutes to about 6 hours,or about 30 minutes, at a temperature of about −20° C. to about 0° C.,or about −10° C. In one embodiment, following addition of the solutionof the compound of formula (IV) or (IVa) in a solvent, the resultingmixture is stirred for about 30 minutes at a temperature of about −10°C. In one embodiment, the reaction is quenched, and, in someembodiments, the resulting product (V) or (Va) is isolated prior to step(d).

In step (d) of Schemes I and Ia, a compound of formula (V) or (Va) iscontacted with a perfluoro acid anhydride and an organic base to form acompound of formula (VI) or (VIa), respectively. Non-limiting examplesof suitable organic bases include pyridine, triethylamine, andcombinations thereof. Examples of suitable perfluoro acid anhydridesinclude trifluoroacetic anhydride, pentafluoropropionic anhydride,heptafluorobutyric anhydride, and combinations thereof. In certainembodiments, the organic base is pyridine and the perfluoro acidanhydride is trifluoroacetic anhydride. In other embodiments, theorganic base is triethylamine, and the perfluoro acid anhydride ispentafluoropropionic anhydride. Suitable solvents for use in step (d)include, but are not limited to acetonitrile, toluene, and combinationsthereof.

More particularly, in certain embodiments, the organic base and theperfluoro acid anhydride are charged into a solution of a compound offormula (V) or (Va) in solvent. The resulting mixture is warmed to about55° C. to about 75° C., or about 55° C., and stirred for about 4 hoursto about 18 hours, or about 6 hours. In one embodiment, the mixture ofperfluoro acid anhydride and the compound of formula (V) or (Va) iswarmed to about 55° C. and stirred for about 4 hours to about 18 hours.In one embodiment, the mixture is stirred for about 6 hours. Uponcompletion of the reaction, in some embodiments, the reaction mixturemay be cooled, and concentrated prior to contacting with a hydroxidesolution to quench excess reagents, and remove the tosyl protectinggroup. Suitable hydroxide solutions include a sodium hydroxide (NaOH)solution, a potassium hydroxide (KOH) solution, and the like. Theresulting mixture may be stirred at room temperature to about 85° C.,including at about 55° C., for about 30 minutes to about 8 hours. In oneembodiment, the mixture is stirred for about 1 hour. Upon completion,the solvent may optionally be removed and switched to methanol, ethanol,isopropanol, or other suitable solvents prior to step (e).

In step (e) of Schemes I and Ia, a compound of formula (VI) or (VIa) isdeprotected, and a pharmaceutically acceptable salt of compound (VII),such as (VIIa), (VIIb), or (VIIc) is formed. The protecting group on thecompound of formula (VI) or (VIa) may be removed using any suitablemeans known in the art. In one embodiment, deprotection occurs bycontacting the compound of formula (VI) or (VIa) with palladium oncarbon (e.g., Pd/C or Pd(OH₂)/C) under hydrogen pressure. In otherembodiments, deprotection occurs by contacting the compound of formula(VI) or (VIa) with an acid. Non-limiting examples of suitable acidsinclude hydrochloric acid (HCl), hydrobromic acid (HBr), hydrobromicacid in acetic acid (e.g., HBr/HOAc), and the like. In otherembodiments, deprotection occurs by subjecting the compound of formula(VI) or (VIa) to heating, e.g., at a temperature of from roomtemperature to about 85° C., including about 50° C. Upon deprotection,the compound of formula (VII) is contacted with the appropriate acid(e.g., hydrochloric acid or p-toluenesulfonic acid) to form thepharmaceutically acceptable salt.

Step (e) may occur in any suitable solvent including, but not limited toethanol, isopropyl acetate, ethyl acetate, and combinations thereof.

More particularly, in some embodiments, palladium on carbon and thecompound of formula (VI) or (VIa) in solvent are mixed under hydrogenpressure at about 1 psig to about 100 psig. In another embodiment, thehydrogen pressure is about 20 psig. The mixture is agitated for about 2hours to about 24 hours, including about 16 hours, at about 20° C. toabout 85° C., including about 50° C. In one embodiment, the mixture isagitated for about 16 hours at about 20° C. to about 80° C. In oneembodiment, the mixture is agitated for about 16 hours at about 50° C.Upon completion of the reaction, the reaction mixture is cooled andfiltered, followed by addition of the appropriate acid. The resultingsalt is optionally isolated prior to step (f).

In step (f), the salt produced in step (e) is reacted with2,2,2-trifluoroethylamine to produce upadacitinib. The step (f) reactionis conducted in the presence of a coupling agent, such ascarbonyldiimidazole (CDI), and optionally buffers, such as dipotassiumphosphate, potassium hydroxide, and combinations thereof. In oneembodiment, the step (f) reaction is conducted in the presence of CDI,dipotassium phosphate, and potassium hydroxide. The step (f) reactionmay be conducted in any suitable solvent including, but not limited to,tetrahydrofuran, ethyl acetate, heptanes, ethanol, water, andcombinations thereof.

More particularly, in certain embodiments, 2,2,2-trifluoroethyl amine isadded slowly (e.g., over 20 minutes) to a slurry of CDI in solvent,while maintaining an internal temperature of less than 30° C. Theresulting solution is stirred for about 10 minutes to about 12 hours,and in one embodiment for about 1 hour, to form an imidazolide solution.The pH of a biphasic mixture of the pharmaceutically acceptable saltfrom step (e) in buffer and solvent is adjusted to about 7 to about 11,and in one embodiment to about 9, by addition of a base. The imidazolidesolution is added, and the resulting mixture is mixed at about 25° C.while maintaining a pH of about 9 by portionwise addition of base forabout 30 minutes to about 18 hours. In one embodiment, the mixtureformed after addition of the imidazolide solution is mixed at about 25°C. while maintaining a pH of about 9 by portionwise addition of base forabout 1 hour. In one embodiment, upon completion, the reaction isquenched and the resulting product isolated.

An alternate process for preparing upadacitinib is illustrated in SchemeII. Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid(I) or a pharmaceutically acceptable salt thereof withtrimethylsulfoxonium chloride gives sulfur ylide (II). Contacting sulfurylide (II) with LiX and a sulfonic acid yields the correspondinghalomethyl ketone (III). Reaction of (III) with (IV) in the presence ofa base yields (V). Cyclization of (V) in the presence of a perfluoroacid anhydride and an organic base produces (VI). Removal of theprotecting group and contacting the deprotected compound (VII) (notshown) with hydrochloric acid yields pharmaceutically acceptable salt(VIIb). The pharmaceutically acceptable salt (VIIb) is converted to thefreebase (VII), which is reacted with 2,2,2-trifluoroethylamine toproduce upadacitinib. Upadacitinib is contacted with L-tartaric acid toform the corresponding tartrate salt, followed by formation of theupadacitinib freebase.

wherein PG, Ts, X, and R1 are as defined above.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In one embodiment, theprotecting group is carboxybenzyl.

In one embodiment, R₁ is —OR₂, and R₂ is ethyl or methyl.

In certain embodiments, a pharmaceutically acceptable salt of thecompound of formula (I) is used in the reaction of step (a). In oneembodiment, the pharmaceutically acceptable salt of the compound offormula (I) is selected from the group consisting of thenaphthalenethane amine salt (Ia) and the dicyclohexylamine salt (Ib).

Steps (a)-(e) of Scheme II are conducted as described above for SchemeI, wherein following deprotection of the compound of formula (VI),deprotected compound (VII) is contacted with hydrochloric acid to formpharmaceutically acceptable salt (VIIb).

In step (f) of Scheme II, salt (VIIb) is contacted with a base to formthe corresponding freebase (VII). Suitable bases include, but are notlimited to hydroxides, such as sodium hydroxide, potassium hydroxide,and the like, and combinations thereof. In one embodiment, the base issodium hydroxide. The reaction of step (f) may be conducted in anysuitable water-containing solvent including, but not limited to, wateralone or in combination with THF, 2-methyl tetrahydrofuran, ethanol,methanol, and the like.

In step (g) compound (VII) is reacted with 2,2,2-trifluoroethylamine toproduce upadacitinib. The step (g) reaction is conducted in the presenceof a coupling agent, such as CDI. Step (g) in Scheme II is conductedusing similar reagents and under similar conditions as those set forthabove for step (f) of Scheme I.

In step (h) of Scheme II, upadacitinib is contacted with L-tartaric acidto form the corresponding tartrate salt (step (h)). Formation of thetartrate salt advantageously aids in removal of impurities prior toisolation of the freebase. The tartrate salt is subsequently convertedback to the freebase form (step (i)) to produce upadacitinib. Inparticular, in step (i) the tartrate salt may be contacted with a base,such as an inorganic base, to produce the corresponding freebase.Suitable bases include, but are not limited to, sodium bicarbonate,sodium carbonate, sodium hydroxide, potassium carbonate, potassiumbicarbonate, potassium hydroxide, and the like, or combinations thereof.In one embodiment, the tartrate salt is contacted with sodiumbicarbonate and sodium carbonate to produce the corresponding freebase.

Suitable solvents for use in step (h) include, but are not limited to,isopropyl acetate, methyl tert-butyl ether, water, isopropyl alcohol,and combinations thereof. Suitable solvents for use in step (i) include,but are not limited to, ethyl acetate, ethanol, water, and combinationsthereof.

In some embodiments, the products of steps (d), (e), (g), and (h) ofScheme II are not isolated prior to the subsequent step.

An alternate process for preparing upadacitinib is illustrated in SchemeIII. Compound (XIa) is hydrogenated to produce (I). Reaction ofprotected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) withtrimethylsulfoxonium chloride gives sulfur yilde (II). Contacting sulfuryilde (II) with an anhydrous source of HBr or HCl yields thecorresponding halomethyl ketone (III). Reaction of (III) with (IV) inthe presence of a base yields (V). Cyclization of (V) in the presence ofa perfluoro acid anhydride and an organic base produces (VI). Removal ofthe protecting group and contacting the deprotected compound with anacid yields a pharmaceutically acceptable salt of (VII). Reacting thepharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamineproduces upadacitinib.

wherein:

PG is a protecting group; X is Br or Cl;

R₁ is selected from the group consisting of alkyl, aryl, and —OR₂;

R₂ is alkyl; and Ts is tosyl.

The protecting group may be any suitable protecting group known in theart. In some embodiments, the protecting group is selected from thegroup consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl,p-methoxybenzyl, and 3,4-dimethoxyenzyl. In another embodiment, theprotecting group is carboxybenzyl.

In another embodiment, R₁ is —OR₂, and R₂ is methyl or ethyl. In suchembodiments, the compound of formula (IV) is a compound of formula(IVa):

wherein R₂ is methyl or ethyl. It has surprisingly been discovered thatwhen R₂ is ethyl or methyl, the compound of formula (V) and subsequentdownstream compounds can be isolated as crystalline solids, which aidsin purification of these intermediates. In contrast, previously knownprocesses, which use compounds where R₂ is t-butyl, result in formationof compounds of formula (V) which are isolated as amorphous solids.

Another process for preparing upadacitinib is illustrated in SchemeIIIa.1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid(XI) is hydrogenated to produce (XII). Reaction of(3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII)with trimethylsulfoxonium chloride gives sulfur yilde (IIa). Contactingsulfur yilde (IIa) with an anhydrous source of HBr yields thecorresponding bromomethyl ketone (IIIa). Reaction of (IIIa) with alkyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamate (IVa) in the presence oflithium tert-butoxide yields (Va). Cyclization of (Va) in the presenceof a perfluoro acid anhydride and an organic base produces (VIa).Removal of the carboxybenzyl protecting group and contacting thedeprotected compound with hydrochloric acid yields the pharmaceuticallyacceptable salt (VIIa). Reacting the pharmaceutically acceptable salt(VIIa) with 2,2,2-trifluoroethylamine produces upadacitinib.

wherein:

Cbz is carboxybenzyl; Ts is tosyl; and R₂ is methyl or ethyl.

In step (a) of Schemes III and IIIa, (XIa) or (XI) (which may beprepared as described in Scheme V) is converted to (I) or (XII),respectively. In particular, in step (a), compound (XI) or (XIa) may becontacted with a catalyst, such as a ruthenium catalyst. Any catalystcomprising a chiral phosphine may be used. One particular example of asuitable catalyst isdiacetato[(S)-(−)5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole]ruthenium(II)(i.e., (S)-Segphos Ru(OAc)₂) Suitable solvents for use in step (a)include, but are not limited to, methanol, triethylamine, andcombinations thereof.

In particular, in certain embodiments, a solution of (XI) or (XIa) andthe catalyst in solvent is hydrogenated at about 30° C. to about 100° C.for from about 1 hour to about 18 hours. In one embodiment, the solutionof (XI) or (XIa) and the catalyst in solvent is hydrogenated at about580 psi. In one embodiment, the solution of (XI) or (XIa) and thecatalyst in solvent is hydrogenated at about 200 psi gauge (psig). Inone embodiment, the solution of (XI) or (XIa) and the catalyst insolvent is hydrogenated at about 80° C. for from about 1 hour to about 8hours, or for about 2 hours, or for about 4 hours. Upon completion, thereaction mixture is cooled to room temperature, filtered, andconcentrated.

The reaction in step (b) of Schemes III and IIIa, is generallyaccomplished in the presence of a coupling agent, such ascarbonyldiimidazole (CDI), and a strong base. The strong base may be,for example, potassium tert-butoxide, sodium tert-butoxide, orcombinations thereof. The step (b) reaction may be conducted in anysuitable solvent including, but not limited to, tetrahydrofuran, water,and methyl tert-butyl ether. In one embodiment, the reaction isconducted in the presence of carbonyldiimidazole and potassiumtert-butoxide.

More particularly, in certain embodiments, a suspension oftrimethylsulfoxonium chloride, strong base, and solvent is heated (e.g.,to about 35° C. to about 65° C., or to about 45° C.) for about 30minutes to about 8 hours, or for about 1 hour, followed by cooling. Inone embodiment, the suspension is cooled to a temperature of about −1°C. or less, or to about −5° C. or less. In some embodiments, theconcentrated filtrate from step (a) is diluted with a suitable solvent(e.g., tetrahydrofuran), and to this solution is slowly added (e.g.,over 30 minutes to 1 hour, or over 30 minutes) CDI. The resultingmixture is stirred at room temperature for 30 minutes to 12 hours, andtypically for about 1 hour. The resulting solution is slowly added(e.g., over 15 minutes to 1 hour, or over 1 hour) to the suspension ofthe trimethylsulfoxonium chloride, strong base, and solvent, whilemaintaining the internal temperature below −1° C. In embodiments, thereaction may be stirred for about 30 minutes to about 8 hours, or forabout 1 hour at a temperature of below about −1° C., or at about −5° C.In another embodiment, the reaction is quenched and the resultingcompound of formula (II) or (IIa) is isolated prior to step (c).

Steps (a) and (b) of Schemes III and IIIa advantageously allow forpreparation of a protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acidwithout formation and isolation of the naphthalenethane amine salt (Ia)or the dicyclohexylamine salt (Ib), or isolation of (I) or (XI).

In step (c) of Schemes III and IIIa, a compound of formula (II) or (IIa)is contacted with an anhydrous source of HBr or HCl to form a compoundof formula (III) or (IIIa), respectively. In particular, the anhydroussource of HBr or HCl comprises no more than 0.2% water (by volume), orno more than about 0.15% water (by volume). The reaction of step (c) maybe conducted in any suitable solvent including, tetrahydrofuran.

More particularly, in certain embodiments, (II) or (IIa) is combinedwith the HBr or HCl in a suitable solvent. In one embodiment, thesolvents are tetrahydrofuran and acetic acid. In one embodiment, thesolvent comprises no more than 0.2% water (by volume). In oneembodiment, (II) or (IIa) is combined with a solvent (e.g., THF) and asolution of HBr in HOAc. The resulting mixture is warmed to about 35° C.to about 65° C., or about 40° C. and agitated. In one embodiment, themixture is agitated for about 4 to about 12 hours, or for about 5 hours.In one embodiment, the mixture is warmed to about 40° C. and agitated(e.g., stirred) for about 5 hours. In one embodiment, the mixture iscooled to room temperature (e.g., around 20° C.) and distilled, followedby washing. In one particular embodiment, the product (compound (III) or(IIIa)) is concentrated to dryness, and resuspended in a solvent (e.g.,N,N-dimethylacetamide) to form a solution of (III) or (IIIa) for use instep (d).

Step (c) advantageously produces the halomethyl ketone (III) or (IIIa)in higher purity than Scheme I or Ia.

In step (d) of Schemes III and IIIa, a compound of formula (III) or(IIIa) is reacted with a compound of formula (IV) or (IVa) (prepared asdescribed herein). The step (d) reaction is conducted in the presence ofa base, such as lithium tert-butoxide, sodium tert-butoxide, orcombinations thereof. In one embodiment, the base is lithiumtert-butoxide. The reaction of step (d) may be conducted in any suitablesolvent including, but not limited to dimethylacetamide,tetrahydrofuran, dichloromethane, ethyl acetate, heptanes, andcombinations thereof.

More particularly, in certain embodiments, the base is slowly added(e.g., over about 30 minutes) to a cooled suspension of the compound offormula (IV) or (IVa) in a solvent. In one embodiment, the suspension ofthe compound of formula (IV) or (IVa) is cooled to about 0° C. Theresulting solution is stirred for about 30 minutes to about 12 hours, orabout 30 minutes, and cooled to about −20° C. to about 0° C., or about−10° C. In one embodiment, the solution is stirred for about 30 minutesand cooled to about −20° C. to about 0° C., or about −10° C. Thehalomethyl ketone solution prepared in step (c) is then slowly added(e.g., over about 1 hour), and the resulting mixture is agitated (e.g.,stirred) for about 30 minutes to about 6 hours, or about 30 minutes, ata temperature of about −20° C. to about 0° C., or about −10° C. In oneembodiment, following addition of the step (c) solution, the resultingmixture is stirred for about 30 minutes at a temperature of about −10°C. In one embodiment, the reaction is quenched, and, in someembodiments, the resulting product (V) or (Va) is isolated prior to step(e).

Steps (e)-(g) of Schemes III and IIIa may be conducted as describedabove for steps (d)-(f) of Scheme I, respectively.

VI. Solid State Forms

The present disclosure also relates to the use of solid state forms ofupadacitinib in the treatment of Crohn's disease and ulcerative colitis.Solid state forms include the Amorphous Freebase form of upadacitinib,Freebase Solvate Form A, Freebase Hydrate Form B, Freebase Hydrate FormC, Tartrate Hydrate, and Freebase Anhydrate Form D. These and othersolid state forms of upadacitinib are described in U.S. patentapplication Ser. No. 15/295,561, which is herein incorporated byreference. The sections below also discuss solid state forms that havebeen identified and selected properties of those solid state forms.

A. Amorphous Freebase

In one embodiment, the solid state form is amorphous upadacitinib (the“Amorphous Freebase”). In one aspect, the Amorphous Freebase comprisesless than about 13% by weight water. In another aspect, the AmorphousFreebase comprises less than about 12% by weight water. In anotheraspect, the Amorphous Freebase comprises less than about 10% by weightwater. In another aspect, the Amorphous Freebase comprises less thanabout 9% by weight water. In another aspect, the Amorphous Freebasecomprises less than about 8% by weight water. In another aspect, theAmorphous Freebase comprises less than about 7% by weight water. Inanother aspect, the Amorphous Freebase comprises less than about 6% byweight water. In another aspect, the Amorphous Freebase comprises lessthan about 5% by weight water. In another aspect, the Amorphous Freebasecomprises less than about 4% by weight water. In another aspect, theAmorphous Freebase comprises less than about 3% by weight water. Inanother aspect, the Amorphous Freebase comprises less than about 2% byweight water. In another aspect, the Amorphous Freebase comprises lessthan about 1% by weight water. In another aspect, the Amorphous Freebasehas a glass transition temperature onset at about 119° C. In anotheraspect, the Amorphous Freebase has a glass transition temperaturemidpoint at about 122° C. In another aspect, the Amorphous Freebase hasa glass transition temperature onset at about 119° C. and a glasstransition temperature midpoint at about 122° C.

The Amorphous Freebase generally has greater solubility, and increasedbioavailability, relative to the corresponding crystalline forms of thecompound. The Amorphous Freebase also has acceptable chemical stability.In addition, the Amorphous Freebase exhibits acceptable stability tolight and peroxide. The Amorphous Freebase, however, is hygroscopic andcan comprise as much as 12% by weight water at 25° C./90% relativehumidity. Environmental controls potentially are required to ensureappropriate control of potency and water content during storage,dispensing, and handling of the Amorphous Freebase.

The Amorphous Freebase can be prepared, for example, using anti-solventcrystallization to prepare the Freebase Solvate Form A or FreebaseHydrate Form B (described below) followed by dehydration or desolvationto yield the Amorphous Freebase. Thiscrystallization/dehydration/desolvation method allows for thelarge-scale manufacture of the Amorphous Freebase without the need forlabor-intensive and expensive techniques such as spray-drying. It alsoprovides for appropriate control of the bulk properties of the AmorphousFreebase (i.e., particle size, flow properties etc.). When the AmorphousFreebase is prepared by desolvation of the Freebase Solvate Form A ordehydration of the Freebase Hydrate Form B, the Amorphous Freebasegenerally retains the morphology of the Freebase Solvate Form A orFreebase Hydrate Form B (i.e., blades with hexagonal crystal faces whenprepared by dehydration of Freebase Hydrate Form B, or irregular whendesolvated from Freebase Solvate Form A).

The process volumes required for crystallization during the large-scalemanufacture of the Freebase Solvate Form A or Freebase Hydrate Form Bgenerally are within conventional processing volumes, but impurityrejection potentially may be lower than desired. Drying anddehydration/desolvation of the Freebase Hydrate Form B/Freebase SolvateForm A to the Amorphous Freebase generally can be carried out withstandard equipment under conventional conditions and the isolatedAmorphous Freebase typically can be co-milled without adverselyimpacting the amorphous state.

B. Crystalline Freebase Solvates and Hydrates

In another embodiment, the solid state form is a crystalline freebase ofupadacitinib. In one aspect, the crystalline freebase is a solvate. Inanother aspect, the crystalline freebase is an isopropyl acetate/watersolvate (the “Freebase Solvate Form A”). In another aspect, thecrystalline freebase is a hydrate (the “Freebase Hydrate Form B”). TheFreebase Solvate Form A and the Freebase Hydrate Form B are furtherdescribed in the Examples of the application.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and that is furthercharacterized by a peak at one or more of 13.7±0.2, 20.8±0.2 and25.0±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, and 20.8±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, and 25.0±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, 20.8±0.2, and 25.0±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees two thetawhen measured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern without a significant peak at one ormore of 15.1±0.2, and 21.7±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 15.1±0.2, and 21.7±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, and without a significant peakat one or more of 15.1±0.2, and 21.7±0.2 degrees two theta, and withouta significant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 15.1±0.2, and21.7±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 3.9±0.2,6.8±0.2, and 14.1±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks at 3.1±0.2,9.3±0.2, and 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees twotheta, and without a significant peak at one or more of 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 15-A±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 15-B±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the crystalline freebase solvate or hydrate has anX-ray powder diffraction pattern characterized by peaks substantially atthe positions listed in Table 17-B±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the crystalline freebase has an X-ray powderdiffraction pattern substantially as shown in FIG. 19.

The Freebase Solvate Form A and Freebase Hydrate Form B are notphysically stable. As discussed above, they desolvate (or dehydrate) andconvert to the Amorphous Freebase upon drying. Although the FreebaseSolvate Form A and Freebase Hydrate Form B generally do not exhibitpharmaceutically acceptable physical stability for use as an activeingredient in a pharmaceutical dosage form, they are usefulintermediates in the preparation of other solid state forms such as theAmorphous Freebase.

C. Crystalline Freebase Hydrate Form C (Hemihydrate)

In another embodiment, the solid state form is a crystalline hydrate,wherein the crystalline hydrate is a hemihydrate. In another embodiment,the solid state form is crystalline hemihydrate of upadacitinib having apowder X-ray diffraction pattern corresponding to Freebase Hydrate FormC. The Freebase Hydrate Form C is further described in the Examples ofthe application.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and that is further characterized by a peakat one or more of 7.7±0.2, 7.9±0.2, 9.6±0.2, 10.3±0.2, 13.9±0.2,15.5±0.2, 15.9±0.2, 17.0±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2,19.3±0.2, 19.7±0.2, 20.5±0.2, 20.9±0.2, 21.9±0.2, 22.2±0.2, 23.5±0.2,24.4±0.2, 24.9±0.2, 28.2±0.2, and 29.5±0.2 degrees two theta whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 17.0±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 20.9±0.2, and 21.7±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern that is characterized by peaks at 13.4±0.2,15.1±0.2, 15.5±0.2, 17.0±0.2, 20.9±0.2, and 21.7±0.2 degrees two thetawhen measured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and21.7±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, and without asignificant peak at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and12.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.9±0.2, 6.8±0.2, and14.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2,15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and12.0±0.2 degrees two theta, and without a significant peak at one ormore of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 15-C±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 17-C±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Freebase Hydrate Form C has an X-ray powderdiffraction pattern substantially as shown in FIG. 20 when measured atabout 25° C. with monochromatic Kα1 radiation.

The Freebase Hydrate Form C generally exhibits good chemical stability,physical stability, and solid state properties (including lowhygroscopicity). Large-scale manufacture of the Freebase Hydrate Form Cis relatively straightforward with minimal scaling, good yield, goodimpurity rejection, fast filtration, conventional drying, and minimalmilling issues (even after subjecting the isolated material to highenergy pinmilling). In addition, different particle sizes can beachieved through appropriate control of the crystallization process.

D. Crystalline Freebase Anhydrate Form D

In another embodiment, the solid state form is a crystalline anhydratefreebase of upadacitinib having a powder X-ray diffraction patterncorresponding to Freebase Anhydrate Form D. The Freebase Anhydrate FormD is further described in the Examples of the application.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and that is furthercharacterized by a peak at one or more of 4.0±0.2, 18.4±0.2, 19.0±0.2,23.0±0.2, and 24.7±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 18.4±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2 and 20.3±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 20.3±0.2, and 23.0±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 20.3±0.2, and 24.7±0.2 degrees two theta, whenmeasured at about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and19.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and19.0±0.2 degrees two theta, and that is further characterized by a peakat one or more of 8.0±0.2, 9.7±0.2, 14.2±0.2, 18.4±0.2, 20.3±0.2,23.0±0.2, and 24.7±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern without a significant peak at one or more of13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two theta, and without asignificant peak at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2degrees two theta, and without a significant peak at one or more of3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2degrees two theta, and without a significant peak at one or more of6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and20.8±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 6.8±0.2, 15.7±0.2, and21.9±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 13.4±0.2, 15.5±0.2, and21.7±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2,14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two theta, andwithout a significant peak at one or more of 3.1±0.2, 9.3±0.2, and20.8±0.2 degrees two theta, and without a significant peak at one ormore of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two theta, and without asignificant peak at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2degrees two theta, when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 15-E±0.2 degrees two theta, when measured atabout 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern characterized by peaks substantially at thepositions listed in Table 15-E±0.2 degrees two theta that have arelative intensity of at least 10.0%, when measured at about 25° C. withmonochromatic Kα1 radiation.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Freebase Anhydrate Form D has an X-ray powderdiffraction pattern substantially as shown in FIG. 22 when measured atabout 25° C. with monochromatic Kα1 radiation.

Freebase Anhydrate Form D is reversibly hygroscopic (up to 1.8% water at90% RH at 25° C.), and is metastable relative to Freebase Hydrate Form Cat typical environmental conditions (e.g., above 2.4% RH at 23° C.) usedduring storage for downstream processing. The manufacture of FreebaseAnhydrate Form D requires strict control of water, as the FreebaseAnhydrate Form D can be manufactured only when the water content of thecrystallization solvent is low (e.g., less than 0.15% at 23° C.,corresponding to a water activity of 2.4%), and will convert to FreebaseHydrate Form C in solutions at high water content. Freebase AnhydrateForm D is slow to crystallize, and difficult to manufacture in higheryield.

E. Crystalline Tartrate

In another embodiment, the solid state form is a tartrate ofupadacitinib. In one aspect, the tartrate is amorphous. In anotheraspect, the tartrate is crystalline. In another aspect, the crystallinetartrate is a solvate. In another aspect, the crystalline tartrate is ahydrate. In another aspect, the tartrate is a crystalline L-tartrate. Inanother aspect, the crystalline L-tartrate is a hydrate. In anotheraspect, the crystalline tartrate is a tetrahydrate (the “TartrateHydrate”). The Tartrate Hydrate (a tetrahydrate) is further described inthe Examples of the application.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta when measured at about 25° C. with monochromatic Kα1radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2, and 25.9±0.2 degrees two theta when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 3.1±0.2, 9.3±0.2,and 12.0±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2 and 9.3±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, when measured at about 25° C. withmonochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 3.1±0.2,9.3±0.2, and 12.0±0.2 degrees two theta, when measured at about 25° C.with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degreestwo theta, and without a significant peak at one or more of 13.4±0.2 and15.1±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta, when measuredat about 25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 13.4±0.2 and 15.1±0.2 degrees two theta, when measured at about25° C. with monochromatic Kα1 radiation.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2,21.9±0.2 degrees two theta, and without a significant peak at one ormore of 13.4±0.2 and 15.1±0.2 degrees two theta, and without asignificant peak at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2degrees two theta.

In further aspects of each of the above embodiments, the significantpeak values have a variation of ±0.1 degrees two theta rather than ±0.2degrees two theta. In still further aspects of each of the aboveembodiments, the significant peak values have a variation of ±0.05degrees two theta rather than ±0.2 degrees two theta.

In one embodiment, the Tartrate Hydrate has an X-ray powder diffractionpattern substantially as shown in FIG. 21, when measured at about 25° C.with monochromatic Kα1 radiation.

The Tartrate Hydrate has acceptable chemical stability and exhibitsacceptable stability to light and peroxide. The Tartrate Hydrate hasgood solubility (BCS Class I) and is not hygroscopic. The TartrateHydrate, however, potentially will convert to an amorphous tartratebelow 10% relative humidity, when heated, or when compressed or undershear.

The Tartrate Hydrate can be manufactured, for example, usinganti-solvent crystallization. Impurity rejection during the large-scalemanufacture of the Tartrate Hydrate generally is good, but scaling maybe greater than desired and specific anti-solvent addition controls andprocess volume restrictions potentially may be required. In addition,appropriate control of the filtration, washing, and drying steps may berequired to minimize consolidation of the wet cake and formation of hardlumps in the isolated material. For example, control of the relativehumidity (e.g., greater than 10% and less than 100% relative humidity),temperature (e.g., crystallization at about 10° C. works well), andmixing rate may be required during drying to minimize the formation ofhard lumps in the isolated material. Insufficient control of the dryingconditions potentially will produce a consolidated, harder material thatmay be difficult to break up during subsequent processing. As previouslynoted, shearing and compression potentially will cause conversion to theamorphous tartrate. The dried material typically is milled withmechanical impact mills (e.g., Fitzmills and pin mills) becauseshear-based mills (e.g., comills) can lead to loss of crystallinity. Inaddition, loss of crystallinity potentially can result from pressure orcompression forces during formulation (such as would be required fortableting).

F. Crystalline Purity

In additional embodiments of the solid state forms discussed above, thesolid state form has a pharmaceutically acceptable crystalline purity(or a pharmaceutically acceptable amorphous purity in the case of theAmorphous Freebase). For example, in one aspect, upadacitinib comprisesat least about 75% by weight of the desired solid state form. In anotheraspect, at least 80% by weight is the desired solid state form. Inanother aspect, at least 85% by weight is the desired solid state form.In another aspect, at least 90% by weight is the desired solid stateform. In another aspect, at least 95% by weight is the desired solidstate form. In another aspect, at least 96% by weight is the desiredsolid state form. In another aspect, at least 97% by weight is thedesired solid state form. In another aspect, at least 98% by weight isthe desired solid state form. In another aspect, at least 99% by weightis the desired solid state form. In another aspect, upadacitinib ispresent as the substantially crystalline pure (or amorphous pure in thecase of the Amorphous Freebase) solid state form. In a preferred aspect,the solid state form is the Amorphous Freebase. In another aspect, thesolid state form is Freebase Anhydrate Form D. In a more preferredaspect, the solid state form is the Freebase Hydrate Form B. In aparticularly preferred aspect, the solid state form is the FreebaseHydrate Form C. In a preferred aspect, the solid state form is theTartrate Hydrate.

VII. Solid State Preparation

The present disclosure also relates to methods for preparing a solidstate form of upadacitinib. In one aspect, the solid state form preparedis the Amorphous Freebase. In another aspect, the solid state formprepared is the Freebase Hydrate Form B. In another aspect, the solidstate form prepared is the Freebase Hydrate Form C. In another aspect,the solid state form prepared is the Tartrate Hydrate. In anotheraspect, the solid state form prepared is the Freebase Anhydrate Form D.

A. Preparation of Amorphous Freebase

The present disclosure relates to methods for preparing the AmorphousFreebase. In one embodiment, the method comprises dehydrating theFreebase Hydrate Form B to provide the Amorphous Freebase. In anotherembodiment, the method comprises desolvating the Freebase Solvate Form Ato provide the Amorphous Freebase. A wide range of process conditionscan be employed for the dehydration/desolvation. The dehydration can beconducted, for example, under ambient conditions or in a vacuum oven.FIG. 14 schematically illustrates one method of preparing the AmorphousFreebase by dehydration of the Freebase Hydrate Form B.

In another embodiment, the method comprises dissolving upadacitinib in asolvent or mixture of solvents; and adjusting the pH of the solvent ormixture of solvents to a pH greater than about 8 to initiateprecipitation of the Amorphous Freebase. In one aspect, the solvent ormixture of solvents comprises water. In another aspect, the pH isadjusted to a pH greater than about 9. In another aspect, the pH isadjusted to a pH greater than about 10. In another aspect, the pH isadjusted to a pH greater than about 11. In another aspect, the pH isadjusted to a pH of at least about 9.

In still other embodiments, the method comprises preparing the AmorphousFreebase using a method selected from the group consisting of impingingjet, spray drying, and hot-melt extrusion.

B. Preparation of Crystalline Freebase Solvate Form A and CrystallineFreebase Hydrate Form B

The present disclosure additionally relates to methods for preparing theFreebase Solvate Form A and Freebase Hydrate Form B. In one embodiment,the method comprises dissolving upadacitinib in a solvent or mixture ofsolvents comprising an anti-solvent; and maintaining the solvent ormixture of solvents at a temperature less than about 15° C. for anamount of time sufficient to initiate crystallization of the FreebaseSolvate Form A or the Freebase Hydrate Form B. The anti-solvent cancomprise, for example, water. The solvent or mixture of solvents cancomprise a polar solvent such as a solvent is selected from the groupconsisting of methanol, ethanol, n-butylamine, acetone, acetonitrile,ethyl formate, methyl acetate, ethyl acetate, methyl ethyl ketone,methyl isobutyl ketone, methyl isobutyl ketone, methyl tert-butyl ether,and isopropyl acetate. The Freebase Solvate Form A and Freebase HydrateForm B exhibit similar PXRD patterns, and are therefore isostructural.The method generally is conducted at sub-ambient temperatures, forexample, less than about 10° C., less than about 5° C., or less thanabout 0° C. In certain aspects, the process further comprises seedingthe solvent or mixture of solvents with crystals of the Freebase SolvateForm A or the Freebase Hydrate Form B.

C. Preparation of Crystalline Freebase Hydrate Form C

The present disclosure additionally relates to methods for preparing theFreebase Hydrate Form C. In one embodiment, the method comprisesdissolving upadacitinib in a solvent or mixture of solvents; andinitiating crystallization to provide the Freebase Hydrate Form C. Thesolvent or mixture of solvents generally will comprise an anti-solvent(such as water) which can be present in the solvent or mixture ofsolvents before, or added to the solvent or mixture of solvents after,the upadacitinib is dissolved in the solvent or mixture of solvents. Thesolvent or mixture of solvents can comprise, for example, one or morepolar solvents (such as polar solvent selected from the group consistingof ethanol and ethyl acetate); one or more nonpolar solvents (such as anonpolar solvent is selected from the group consisting of hexane andheptane); or at least one polar solvent and at least one nonpolarsolvent. In one aspect, the solvent or mixture of solvents is a ternarysolvent mixture comprising ethyl acetate, heptane, and water. The methodgenerally is conducted at temperatures less than about 30° C., less thanabout 20° C., or less than about 10° C. In certain aspects, theinitiating crystallization step comprises mixing the solvent or mixtureof solvents to provide sufficient agitation to initiate crystallization.In certain aspects, the initiating crystallization step comprisesseeding the solvent or mixture of solvents with crystals of the FreebaseHydrate Form C. In certain aspects, the initiating crystallization stepcomprises both mixing the solvent or mixture of solvents and seeding thesolvent or mixture of solvents with crystals of the Freebase HydrateForm C.

In one embodiment, upadacitinib is first prepared according to any ofthe methods set forth herein, a reaction mixture comprising upadacitinibis filtered, and the resulting solution is suspended in a solvent ormixture of solvents. The solvent or mixture of solvents can comprise,for example, one or more polar solvents (such as polar solvent selectedfrom the group consisting of ethanol and ethyl acetate); one or morenonpolar solvents (such as a nonpolar solvent is selected from the groupconsisting of hexane and heptane); or at least one polar solvent and atleast one nonpolar solvent. In one particular embodiment, the solvent isethyl acetate, or a mixture of ethyl acetate and water. In certainaspects, the initiating crystallization step comprises seeding thesolvent or mixture of solvents with crystals of the Freebase HydrateForm C. In one particular aspect, the crystallization occurs in a wetmill.

FIG. 15 schematically illustrates one method of preparing the FreebaseHydrate Form C.

D. Preparation of Crystalline Freebase Anhydrate Form D

The present disclosure additionally relates to methods for preparing theFreebase Anhydrate Form D. In one embodiment, the method comprisesdissolving upadacitinib in a solvent or mixture of solvents; andinitiating crystallization to provide the Freebase Anhydrate Form D. Thesolvent or mixture of solvents will be water-free, or close towater-free. In embodiments, the solvent or mixture of solvents will havea water content of less than about 0.15 wt %, or less than about 0.10wt. %, or less than about 0.05 wt. %, or about 0 wt. % at 23° C. In oneembodiment, the solvent or mixture of solvents will have a wateractivity of about 2.4% or less, or about 2.2% or less, or about 2.0% orless, or about 1.5% or less. The solvent or mixture of solvents cancomprise, for example, ethyl acetate (EtOAc), heptane, and combinationsthereof. In one embodiment, the solvent system comprises a mixture ofheptane in ethyl acetate. In some embodiments, the solvent systemcomprises about 10 wt. %, or about 20 wt. %, or about 30 wt. %, or about40 wt. % heptane in ethyl acetate. The method generally is conducted attemperatures of at least about 7° C., at least about 23° C., at leastabout 25° C. or less, or at least about 30° C. In one embodiment, themethod is conducted at about 23° C. In certain aspects, the initiatingcrystallization step comprises mixing the solvent or mixture of solventsto provide sufficient agitation to initiate crystallization. In certainaspects, the initiating crystallization step comprises seeding thesolvent or mixture of solvents with crystals of the Freebase AnhydrateForm D. In certain aspects, the initiating crystallization stepcomprises both mixing the solvent or mixture of solvents and seeding thesolvent or mixture of solvents with crystals of the Freebase AnhydrateForm D.

E. Preparation of Crystalline Tartrate Hydrate

The present disclosure additionally relates to methods for preparing theTartrate Hydrate. In one embodiment, the method comprises dissolvingupadacitinib and L-tartaric acid in a solvent or mixture of solvents toform a crystallization solution; and crystallizing the Tartrate Hydratefrom the crystallization solution. The solvent or mixture of solventscan comprise, for example, water and/or, for example, one or more polarsolvents (such as isopropyl acetate). The solvent or mixture of solventsalso can comprise an anti-solvent (such as isopropyl acetate). Incertain aspects, the process further comprises seeding the solvent ormixture of solvents with crystals of the Tartrate Hydrate.

The crystallization generally is conducted at a temperature less thanabout 40° C. When an anti-solvent is used, a moderate rate of additionis employed for the anti-solvent as a faster rate of addition typicallyresults in the precipitation of an amorphous tartrate and a slower rateof addition allows the resulting slurry to thicken. Proper control offiltration, washing, and drying may be needed to avoid potential issuesassociated with consolidation of the filter cake, including solvententrapment, solid properties (e.g., hard, chunky solids) and handing,and damage to equipment. Depending upon the properties of the driedTartrate Hydrate material, milling may require a mechanical impact-typeof mills rather than a shear-based mill (such as a co-mill).

FIG. 16 schematically illustrates one method of preparing the TartrateHydrate.

VIII. Pharmaceutical Compositions and Routes of Administration

One or more compounds of this disclosure can be administered to a humanpatient by themselves or in pharmaceutical compositions where they aremixed with biologically suitable carriers or excipient(s) at doses totreat or ameliorate a disease or condition as described herein. Mixturesof these compounds can also be administered to the patient as a simplemixture or in suitable formulated pharmaceutical compositions.

The pharmaceutical compositions of the present disclosure may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentdisclosure thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

In one embodiment, the active ingredient contained in the dosage unitcomposition is upadacitinib, or a pharmaceutically acceptable salt orsolid state form thereof. In one embodiment, the target or label amountof active ingredient (e.g., upadacitinib) provided for inclusion in thecompositions of the present disclosure refers to the amount ofupadacitinib freebase. For instance, upadacitinib may be prepared inseveral solid state forms including Amorphous Freebase, crystallinesolvates and hydrates (e.g., Freebase Solvate Form A, Freebase HydrateForm B), crystalline hemihydrates (e.g., Freebase Hydrate Form C),crystalline anhydrate (e.g., Freebase Anhydrate Form D), and crystallinetartrate (e.g., Tartrate Hydrate). Preparation of these solid stateforms is described herein and also in U.S. patent application Ser. No.15/295,561, which is herein incorporated by reference. It should beunderstood that in embodiments, where the dosage unit compositioncomprises, e.g., a solvate, hydrate, hemihydrate, or tartrate ofupadacitinib, the amount of solvate, hydrate, hemihydrate, or tartrateof upadacitinib present in the dosage unit composition may be slightlyhigher than the target amount of upadacitinib (active ingredient), andpreferably will be present in the dosage unit composition in an amountsufficient to deliver the target amount of upadacitinib freebaseequivalent to a patient. For example, if the target amount ofupadacitinib (active ingredient) in a dosage unit composition is 15 mg,a dosage unit composition comprising, for example, a hydrate ofupadacitinib, may comprise the hydrate in an amount sufficient todeliver 15 mg of the upadacitinib freebase equivalent.

In one embodiment, the pharmaceutical composition is a tablet dosageform. In one aspect, the tablet is coated with a pharmaceuticallyacceptable polymer. In one embodiment, the pharmaceutical composition isa capsule dosage form.

In one embodiment, tablet is a controlled-release formulation, such asan extended release tablet dosage form (also referred to herein as amodified release or sustained release formulation). Such formulationspermit the sustained release of the active ingredient over an extendedperiod of time, as compared to immediate release solid dosage forms,which permit the release of most or all of the active ingredient over ashort period of time (e.g., typically around 60 minutes or less). In oneaspect, the tablet comprises an active ingredient (e.g., upadacitinib)and at least one additive selected from the group consisting of arelease control polymer, a filler, a glidant, a lubricant (e.g., for usein compacting the granules), a pH modifier, a surfactant, andcombinations thereof. In one aspect, the tablet comprises an activeingredient, a release control polymer, a filler, a glidant, and alubricant. In one aspect, the tablet comprises an active ingredient, arelease control polymer, a filler, a glidant, a lubricant, and a pHmodifier.

In certain embodiments, the release control polymer will be ahydrophilic polymer. Examples of suitable release control polymersinclude, but are not limited to a cellulose derivative with a viscosityof between 1000 and 150,000 mPA-s, hydroxypropylmethyl cellulose (e.g.,Hypromellose 2208 or controlled release grades of hydroxypropylmethylcellulose, including the E, F, and K series), copolymers of acrylic acidcrosslinked with a polyalkenyl polyether (e.g., Carbopol® polymers),hydroxypropyl cellulose, hydroxyethyl cellulose, non-ionic homopolymersof ethylene oxide (e.g., Polyox™), water soluble natural gums ofpolysaccharides (e.g., xanthan gum, alginate, locust bean gum, etc.),crosslinked starch, polyvinyl acetates, polyvinylpyrrolidone, mixturesof polyvinyl acetates and polyvinyl pyrrolidone, and combinationsthereof. In one embodiment, the release control polymer is selected fromthe group consisting of hydroxypropylmethyl cellulose, copolymers ofacrylic acid crosslinked with a polyalkenyl polyether (e.g., Carbopol®polymers), and combinations thereof. Examples of suitable fillers(“bulking agents”) include, but are not limited to, microcrystallinecellulose (e.g., Avicel® PH 101; Avicel® PH 102;), mannitol (e.g.,Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, andthe like. In one embodiment, the filler is selected from the groupconsisting of microcrystalline cellulose, mannitol, and combinationsthereof. Examples of suitable glidants include, but are not limited to,silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate,magnesium silicate, talc, and combinations thereof. In one embodiment,the glidant is colloidal silicone dioxide. Examples of suitablelubricants include, but are not limited to, polyethylene glycol (e.g.,having a molecular weight of from 1000 to 6000), magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, and the like. In oneembodiment, the lubricant is magnesium stearate. Examples of suitable pHmodifiers include, but are not limited to, organic acids, such astartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate;magnesium or calcium carbonate or bicarbonate; and combinations thereof.In one embodiment, the pH modifier is tartaric acid. Examples ofsuitable surfactants include sodium lauryl sulfate.

In one embodiment, the pharmaceutical composition comprises from about10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaricacid, fumaric acid, citric acid, succinic acid, malic acid, orcombinations thereof. In other embodiments, the formulation comprisesfrom about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %,about 15 w/w. %, about 20 w/w %, about 25 w/w % or about 30 w/w % pHmodifier. In one embodiment, the pH modifier is tartaric acid. Sustainedpeak plasma concentrations can theoretically be achieved by means ofsustained release matrix systems. However, when such systems are made ofhydrophilic polymers, such as HPMC, they seldom provide pH independentdrug release of pH-dependent soluble drugs, and they are normallyincapable of attaining zero-order release except for practicallyinsoluble drugs. Is has been discovered that when a pH modifier, such astartaric acid, fumaric acid, citric acid, succinic acid, malic acid, orcombinations thereof, is used in a hydrophilic sustained release matrixsystem, it allows upadacitinib or a pharmaceutically acceptable salt orsolid state form thereof to be released at a steady rate regardless ofthe pH of the environment. It has been discovered that as a tabletcontaining the hydrophilic polymer matrix system erodes, upadacitinibreacts with the HPMC, creating a thicker gel layer which slows therelease of upadacitinib from the tablet. The resulting gel layerprovides an environment suitable for upadacitinib to dissolve.

Thus, in one embodiment, the pharmaceutical composition of the presentdisclosure exhibits a pH-independent release of the active ingredient(upadacitinib). Advantageously, it has been discovered that includingorganic acids, such as a tartaric acid, in the composition as a pHmodifier improves the release profile, and results in a pH independentrelease of the active ingredient. Without wishing to be bound to anyparticular theory, it is believed that the pH modifier and hydrophilicpolymer create a microenvironment in which the active ingredientdissolves, and then is released. The release from the microenvironmentoccurs at approximately the same rate, regardless of pH. This isparticularly advantageous, since the pH of the gastrointestinal tractmay vary significantly from the stomach (e.g., pH of about 1.5-3), tothe duodenum (e.g., pH of about 4-5), to the lower part of the smallintestines (e.g., pH of about 6.5-7.5).

Thus, in one embodiment, the pharmaceutical composition is a modifiedrelease formulation comprising upadacitinib, or a pharmaceuticallyacceptable salt or solid state form thereof, a hydrophilic polymer, anda pH modifier, wherein the hydrophilic polymer, in contact with water,forms a gel layer that provides an environment suitable forupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, to dissolve. In some embodiments, the environment suitable forupadacitinib, or a pharmaceutically acceptable salt or solid state formthereof, to dissolve has a pH equal to or less than about 3.8 at 37° C.In some such embodiments, the environment has a pH of from about 1.5 toabout 3.7, or from about 2.0 to about 3.7, or from about 2.5 to about3.6, or from about 3.0 to about 3.6, or from about 3.0 to about 3.5.

In one such embodiment, the environment suitable for upadacitinib, or apharmaceutically acceptable salt or solid state form thereof, todissolve is as set forth above, and the modified release formulationcomprises from about 10 w/w % to about 35 w/w % of a pH modifier, and inparticular, tartaric acid, fumaric acid, citric acid, succinic acid,malic acid, or combinations thereof. In other embodiments, theformulation comprises from about 20 w/w % to about 35 w/w %, or fromabout 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w%, or about 10 w/w %, about 15 w/w %, about 20 w/w %, about 25 w/w % orabout 30 w/w % pH modifier. In any of these embodiments, the pH modifiermay be selected from the group consisting of tartaric acid, fumaricacid, citric acid, succinic acid, malic acid, and combinations thereof.In one such embodiment, the pH modifier is selected from the groupconsisting of tartaric acid, fumaric acid, citric acid, succinic acid,and combinations thereof. In one such embodiment, the pH modifier isselected from the group consisting of tartaric acid and fumaric acid. Inone embodiment, the pH modifier is tartaric acid. In one embodiment, thepH modifier is fumaric acid or citric acid. The weight % tartaric acidset forth herein is by weight of the uncoated composition (e.g.,uncoated tablet). In any of the foregoing embodiments, the hydrophilicpolymer may be a cellulose derivative with a viscosity of between 1000and 150,000 mPA-s. In one embodiment, the hydrophilic polymer isselected from the group consisting of hydroxypropylmethyl cellulose,hydroxyethyl cellulose, and mixtures or combinations thereof. In oneembodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose. Inone embodiment, the hydrophilic polymer is hydroxypropylmethyl celluloseGrade E, F, or K. In one embodiment, the hydrophilic polymer isHypromellose 2208.

In one embodiment, the tablet is a compressed and/or milled tablet. Forexample, in some embodiments, the tablet is formed by blending thecomposition components (e.g., including the active ingredient and atleast one pharmaceutically acceptable carrier). The composition can thenbe either directly compressed, or one or more of the compositioncomponents can be granulated prior to compression. In one embodiment,milling is performed using a mill fitted with any suitable size screen(e.g., a fitted with a screen size of from about 600 to about 1400 μm orabout 610 μm or about 1397 μm). Compression can be done in a tabletpress, such as in a steel die between two moving punches.

In other embodiments, the compressed and/or milled tablet is formulatedusing a wet granulation process. Use of wet granulation helps reduceand/or eliminate sticking that may occur when compression without wetgranulation (e.g., direct compression) is used to formulate the tablets.In one embodiment, the wet granulation process may include the followingsteps: (a) combining the active ingredient (e.g., upadacitinib or apharmaceutically acceptable salt or solid state form thereof or a solidstate form of upadacitinib) and at least a portion of one additionalcomposition component to form a dry granulation mixture; (b) contactingthe dry granulation mixture with a granulation fluid to form a wetgranulation mixture; (c) drying the wet granulation mixture to form agranulated material; (d) milling the granulated material to form amilled granulated material; (e) combining the milled granulationmaterial with the remaining composition components; and (f) compressingthe composition into the solid dosage unit (e.g., a tablet).

In step (a) of this process, the active ingredient may be combined with,for example, a portion of the release control polymer (e.g., HPMC), aportion of the filler (e.g., microcrystalline cellulose, such as Avicel®PH101), or both a portion of the release control polymer and a portionof the filler to form the dry granulation mixture. Any suitable portionof the release control polymer may be used in step (a). In oneembodiment, from about 5 to 10 wt. % or from about 6 to 8 wt. % of thetotal amount of the release control polymer in the composition is usedin step (a).

In certain embodiments, the granulation fluid used in step (b) maycomprise water, a suitable solvent (e.g., ethanol, isopropanol, etc.),or combinations thereof. In one embodiment, the granulation fluidcomprises water. In one embodiment, the active ingredient may becombined with a portion of the filler, while a portion of the releasecontrol polymer (e.g., HPMC) is dissolved in a liquid, such as water, toform the granulation fluid. In one embodiment, the granulation fluid issprayed on the dry granulation mixture.

The dried granulation material may be milled using, for example, acomill fit with any suitable screen size. In one embodiment, the screensize is from about 600 to about 900 microns, or from about 610 to about813 microns. In one embodiment, the granulated material is milled usinga comill fitted with a 610 μm screen. In one embodiment, the granulatedmaterial is milled using a comill fitted with a 813 μm screen.

In step (e), the milled granulation material is combined with anyremaining composition components, such as any remaining filler (e.g.,microcrystalline cellulose, such as Avicel® PH102), any remainingrelease control polymer, glidants, lubricants, pH modifiers,surfactants, and the like. In one embodiment, the filler and/or releasecontrol polymer included in the granulated material may be the same ordifferent than the filler and/or release control polymer added in step(e). For instance, in one embodiment, the filler included in thegranulated material (e.g., Avicel® PH101) may have a smaller particlesize distribution than the filler added in step (e) (e.g., Avicer®PH102).

In one embodiment, the composition may be sieved, and the sievedcomposition blended, for example, after step (e), and prior tocompressing the composition (step (f)). In one embodiment, theformulation is sieved prior to addition of any lubricant. In oneembodiment, the pH modifier (e.g., tartaric acid) is optionally milledprior to combining with the granulated material.

In some embodiments, the tablet further comprises a film coat. A filmcoat on the tablet further may contribute to the ease with which it canbe swallowed. A film coat can also improve taste and provides an elegantappearance. In certain embodiments, the film-coat includes a polymericfilm-forming material such as hydroxypropyl methylcellulose,hydroxypropylcellulose, and acrylate or methacrylate copolymers. Besidesa film-forming polymer, the film-coat may further comprise aplasticizer, e.g. polyethylene glycol, a surfactant, e.g. polysorbates,and optionally a pigment, e.g. titanium dioxide or iron oxides. Thefilm-coating may also comprise talc as anti-adhesive. In one embodiment,the film coat accounts for less than 5% by weight of a pharmaceuticalcomposition of the present disclosure.

In another embodiment, the pharmaceutical composition is a capsuledosage form.

For the prevention or treatment of disease, the appropriate dosage ofJAK1 inhibitor will depend on a variety of factors such as the type ofdisease to be treated, as defined above, the severity and course of thedisease, whether the JAK1 inhibitor is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the antibody, and the discretion of the attendingphysician. The JAK1 inhibitor is suitably administered to the patient atone time or over a series of treatments.

The JAK1 inhibitor is formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being, treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the scheduling of administration, and otherfactors known to medical practitioners. The “therapeutically effectiveamount” of the JAK1 inhibitor will be governed by such considerations.

Pharmaceutical compositions suitable for use in the present disclosureinclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount effective to preventdevelopment of or to alleviate the existing symptoms of the patientbeing treated. Determination of the effective amounts is well within thecapability of those skilled in the art. In one particular embodiment,the composition will be a once-daily modified release formulationcomprising 7.5 mg, 15 mg, 30 mg, or 45 mg of upadacitinib or apharmaceutically acceptable salt or solid state form thereof.

IX. Examples Example 1: Preparation of Amorphous Freebase

A. Method A: Precipitation from Water

Upadacitinib (approximately 300 g) was dissolved in water (10 L) and 50%sodium hydroxide (160 g) was added drop-wise over a two hour period toadjust the pH to greater than 12. Solids formed immediately. The solidswere filtered, washed with two 500 mL aliquots of water, and then driedin a vacuum oven. The solids were equilibrated for a short period oftime at ambient temperature prior to characterization. Conversion toAmorphous Freebase of upadacitinib was confirmed by PXRD analysis.

B. Method B: Dehydration of Freebase Hydrate Form B

A sample of the Freebase Hydrate Form B form of upadacitinib(crystallized from ethanol/water at sub-ambient temperatures asdescribed in Example 2, Method C below) was placed in a vacuum oven at40° C. overnight. The solids removed from the vacuum oven wereequilibrated for a short time at 23° C. prior to characterization.Conversion to Amorphous Freebase of upadacitinib was confirmed by PXRDanalysis.

Example 2: Preparation of Freebase Solvate Form A and Freebase HydrateForm B

A. Method A: Freebase Solvate Form A (Isopropyl Acetate/Water Solvate)

A sample of the Amorphous Freebase of upadacitinib (25 mg) was added toa vial followed by isopropyl acetate (125 μL) and water (10 μL). Allsolids dissolved at ambient temperature. The solution was placed in afreezer at −16° C. for 4 days. The liquor was decanted and thecrystallized solids were isolated. The isolated crystals were analyzedby PXRD while still wet. Conversion to Freebase Solvate Form A(isopropyl acetate/water solvate) of upadacitinib was confirmed by PXRDanalysis.

B. Method B: Freebase Hydrate Form B from Methanol/Water

A sample of the Amorphous Freebase of upadacitinib (164 mg) and MeOH(621 mg) were added to a vial. The components were mixed at ambienttemperature until the solids dissolved. Water (approximately 680 μL) wasadded to the vial and the vial was placed in an ice/sodium chloride bathat approximately −3° C. Crystal seeds comprising Freebase Hydrate Form Bwere added to the vial and the vial was placed in a freezer at −16° C. Asample was pulled from the crystallized suspension and the solids wereimmediately analyzed with PXRD and TGA-MS. Conversion to FreebaseHydrate Form B of upadacitinib was confirmed by PXRD and TGA-MSanalysis.

C. Method C: Freebase Hydrate Form B from Ethanol/Water

A sample of the Amorphous Freebase of upadacitinib (4.2 g) was dissolvedin EtOH (15.3 g) in a jacketed reactor. Water (23.3 g) was slowly addedto the reactor. The reactor solution was cooled to approximately 2° C. Asmall portion of a seed solution comprising the Freebase Hydrate Form Bwas charged to the reactor. The suspension was mixed at approximately 2°C. for 3 hours and water (36 g) in was charged to the reactor in smallaliquots over several hours while maintaining the suspension at atemperature of approximately 2° C. The crystallized suspension was mixedat approximately 2° C. and the solids were isolated via filtration.Conversion to Freebase Hydrate Form B of upadacitinib was confirmed byPXRD analysis.

The Freebase Solvate Form A and Freebase Hydrate Form B do not readilycrystallize from solution. In general, sub-ambient temperatures andsufficient water activity are needed to crystallize Freebase SolvateForm A and Freebase Hydrate Form B from solution.

Crystalline freebase hydrates and solvates have been isolated fromseveral solvent systems either through primary nucleation (withoutseeding) or through seeding. In addition to crystallization fromisopropyl acetate/water (as described in Method A above), crystallinefreebase hydrates or solvates also have been isolated through primarynucleation (without seeding) from, e.g., n-butylamine/water andethanol/water solvent systems. In addition to crystallization frommethanol/water (as described in Method B above) and ethanol/water (asdescribed in Method C above), crystalline freebase hydrates or solvatesalso have been isolated through seeding from, e.g., acetone/water;acetonitrile/water; ethyl formate/water; methyl acetate/water; ethylacetate/water; methyl ethyl ketone/water; methyl isobutyl ketone/water,methyl isobutyl ketone/methyl tert-butyl ether/water; and isopropylacetate/methyl tert-butyl ether/water solvent systems. The FreebaseSolvate Form A (isopropyl acetate/water solvate) prepared in Method Aabove, the Freebase Hydrate Form B prepared in Methods B and C above,and these other crystalline freebase solvates or hydrates that have beenprepared are isostructural and exhibit similar PXRD patterns. Notably,these crystalline freebase solvates and hydrates are distinguishablefrom and exhibit a different PXRD pattern than Freebase Hydrate Form C(a hemihydrate), which is described below.

The Freebase Solvate Form A and Freebase Hydrate Form B that wereprepared were not stable after isolation at ambient conditions andreadily dehydrated to the Amorphous Freebase.

Example 3: Preparation of Freebase Hydrate Form C

A. Method A: Freebase Hydrate Form C from Ethanol/Water

A sample of the Amorphous Freebase of upadacitinib (2 g) was transferredto a 500 mL beaker equipped with a stirring bar. EtOH (50 g) was addedto the beaker and stirred until all solids dissolved. The solution wastransferred to a 250 mL jacketed flask equipped with a dispersingdevice. The solution was cooled to 6° C. Water (150 g) was added to thesolution and the solution was subjected to high shear for two hoursusing the dispersing device. After solid formation was observed, anadditional amount of water (50 g) was added to the resulting suspension.The suspension was held overnight at ambient temperature. Solids wereisolated and examined on the following day. Conversion to upadacitinibFreebase Hydrate Form C was confirmed by PXRD analysis.

B. Method B: Freebase Hydrate Form C From Ethyl Acetate/Heptane/Water

A crude reaction mixture assaying for 11.1 g of upadacitinib was takenup in 2% water in EtOAc (70 g) and seeded with Freebase Hydrate Form C(100 mg). The suspension was stirred overnight and heptane (70 g) wasadded. The solids were collected by filtration, washed with watersaturated EtOAc/heptane (1/1, 100 mL), and dried under vacuum at 50° C.Conversion to upadacitinib Freebase Hydrate Form C was confirmed by PXRDanalysis.

As was observed with the Freebase Solvate Form A and the FreebaseHydrate Form B, the Freebase Hydrate Form C also does not readilycrystallize from solution.

Example 4: Preparation of Tartrate Hydrate

Three methods for the preparation of upadacitinib tartrate tetrahydrate(the “Tartrate Hydrate”) are described below. Method A describes aninitial procedure that was used to prepare the tartrate tetrahydrate.Method B describes a modified procedure used to prepare the tartratetetrahydrate at a larger scale. Method C describes a further modifiedprocedure used to prepare the tartrate tetrahydrate. The modifiedprocedure of Method C relative to the procedure of Method B furtherreduces solidification of the filter cake, a potential problem thatpotentially can impact manufacturability and downstream processing.

A. Method A

A sample of the Amorphous Freebase of upadacitinib (28.2 mg) wastransferred to an amber vial. Water (200 μL) and L-tartaric acid (34.5mg (approximately 3 equivalents)) were added to the vial. The suspensionwas vortexed under ambient conditions until all the solids dissolved.The solution in the vial was magnetically stirred at 0° C. The followingday, the solids were isolated from the solution and left at ambienttemperature for a short period of time prior to characterization.Conversion to the upadacitinib Tartrate Hydrate (tetrahydrate) wasconfirmed by PXRD analysis.

B. Method B

Upadacitinib (4.6 g) was added to a jacketed reactor followed by theaddition of isopropanol (6.5 mL) and IPAc (7.8 mL). The slurry was mixedat ambient condition until the solids dissolved. In a separate vial,L-tartaric acid (1.96 g) was dissolved in deionized water (3.92 mL). TheL-tartaric acid solution was added to the reactor followed by theaddition of tartrate tetrahydrate seed crystals (28 mg). The suspensionwas mixed for 30 minutes under ambient conditions. IPAc (71 mL) wasadded in small aliquots over 2 hours. The crystallized suspension wascooled to 5° C. and equilibrated at 5° C. overnight. The suspension wasdischarged onto a filter and the filter cake rinsed with 20 mL of watersaturated IPAc. The filtered solids were air-dried for two days.Conversion to the upadacitinib Tartrate Hydrate (tetrahydrate) wasconfirmed by PXRD analysis.

C. Method C

Crystallization: Upadacitinib (104 g) was added to a flask together withisopropanol (222.7 g) and IPAc (375.8 g). The components were mixedunder ambient conditions until the solids dissolved. In a separateflask, L-tartaric acid (61.6 g) was dissolved in water (98.3 g). Thecontents of the two flasks were then added to a jacketed reactor.Tartrate tetrahydrate seed crystals (1.55 g) were added to the reactorsolution. The resulting suspension was mixed overnight under ambientconditions. IPAc (2542 g) was charged to the reactor suspension over an8 hour period.

Filtration, Washing and Drying: Approximately half of the crystallizedtartrate suspension was charged to a jacketed agitated filter dryer. Thesuspension was cooled inside the filter dryer to approximately 11° C.The suspension was filtered using positive pressure until a wet cake wasobtained. Water saturated IPAc (438 g) was charged to the filter dryerand the suspension was mixed overnight at approximately 11° C. Thesuspension was filtered using positive pressure until a wet cake wasobtained. Water saturated MTBE (110 g) was charged to the filter dryer.After 10 minutes, the suspension was filtered with positive pressureuntil a wet cake was obtained. Water saturated MTBE (261 g) was chargedto the filter dryer and the suspension was mixed at approximately 11° C.for 3.5 hours. The suspension was filtered with agitation using positivepressure until a wet cake was obtained. The wet cake was dried withconstant agitation at a temperature of approximately 11° C. underhumidified nitrogen and positive pressure for two days. Conversion tothe upadacitinib Tartrate Hydrate (tetrahydrate) was confirmed by PXRDanalysis.

Example 5: Preparation of Freebase Anhydrate Form D

A sample of the Amorphous Freebase of upadacitinib was dissolved inwater-free EtOAc at a concentration of 19.6% (w/w). An aliquotcomprising approximately 1 mL was transferred to a 4 mL vial equippedwith a magnetic stirrer. The vial was sealed with parafilm and mixed at400 rpm on a magnetic stir plate at around 23° C. for almost 8 weeks.The resulting slurry was filtered and left at ambient conditions for ashort period of time prior to characterization. Conversion to FreebaseAnhydrate Form D was confirmed by PXRD analysis.

Example 6: Microscopy/Crystal Morphology

The solid state forms of upadacitinib were evaluated by microscopy.Samples were examined by microscopic visual examination using apolarizing microscope (model Eclipse E-600 POL, Nikon Corp., GardenCity, N.Y.). A color video camera was used to record digital images(model DXC 390, Fryer Co., Inc., Huntley, Ill.). Images were capturedusing MetaMorph Imaging System (version 4.6R8, Universal ImagingCorporation, Downingtown, Pa.). Observations regarding the crystalmorphology of the samples are reported in Table 14 below. Those of skillin the art will recognize that variation in crystal shape and size maybe observed depending upon the specific crystallization conditionsemployed. The solvation states and PXRD profiles reported in Table 14correspond to the information presented in the figures and subsequentexamples of this application.

TABLE 14 Solid Form Solvation/ Nomenclature Species Hydration StateMorphology Amorphous Freebase Anhydrous Blades (when Freebase preparedvia precipitation or dehydration of Freebase Hydrate Form B) FreebaseSolvate Freebase Isopropyl Acetate/ Irregular Form A Water SolvateFreebase Hydrate Freebase Labile Hydrate Blades Form B Freebase HydrateFreebase Hemihydrate Prisms Form C Tartrate Hydrate TartrateTetrahydrate Needles Freebase Freebase Anhydrous Not DeterminedAnhydrate Form D

Example 7: PXRD Analysis

The solid state forms of upadacitinib listed in Table 14 were analyzedby X-ray powder diffraction (“PXRD”). The PXRD data were collected witha G3000 diffractometer (Inel Corp., Artenay, France) equipped with acurved position sensitive detector and parallel beam optics. Thediffractometer was operated with a copper anode tube (1.5 kW fine focus)at 40 kV and 30 mA. An incident beam germanium monochromator providedmonochromatic Kα1 radiation λ=1.540562 Å). The diffractometer wascalibrated using the attenuated direct beam at one-degree intervals.Calibration was checked using a silicon powder line position referencestandard (NIST 640c). Samples were prepared by spreading the samplepowder in a thin layer on an aluminum sample holder and gently levelingwith a glass microscope slide. The instrument was computer controlledusing the Symphonix software (Inel Corp., Artenay, France) and the datawas analyzed using the Jade software (version 6.5, Materials Data, Inc.,Livermore, Calif.). The aluminum sample holder was mounted on therotating sample holder of the G3000 diffractometer and the diffractiondata collected at ambient conditions.

Tables 15-A through 15-E set out the significant parameters of the mainpeaks in terms of 2Θ values and intensities for the crystalline formsanalyzed. It is known in the art that an X-ray powder diffractionpattern may be obtained which has one or more measurement errorsdepending on measurement conditions (such as equipment, samplepreparation or machine used). In particular, it is generally known thatintensities in an X-ray powder diffraction pattern may fluctuatedepending on measurement conditions and sample preparation. For example,persons skilled in the art of X-ray powder diffraction will realize thatthe relative intensities of peaks may vary according to the orientationof the sample under testing and on the type and setting of theinstrument used. The skilled person also will realize that the positionof reflections can be affected by the precise height at which the samplesits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample also may have aneffect on the results. A person skilled in the art will appreciate thatthe diffraction pattern data presented below is not to be construed asabsolute and any crystalline form that provides a power diffractionpattern substantially identical to those disclosed below fall within thescope of the present disclosure (for further information see Jenkins, R& Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’, JohnWiley & Sons, 1996).

The PXRD pattern corresponding to the Amorphous Freebase (viaprecipitation) and the Amorphous Freebase (via dehydration) are shown inFIGS. 17A and 17B, respectively.

The PXRD pattern corresponding to the Freebase Solvate Form A is shownin FIG. 18. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 15-A below.

TABLE 145A PXRD Peak Listing Freebase Solvate Form A (IsopropylAcetate/Water Solvate) PEAK POSITION (°2Θ) RELATIVE INTENSITY 3.1 100.05.4 15.4 6.6 10.7 8.2 8.7 9.4 74.7 10.8 9.2 11.1 6.7 12.1 33.5 13.1 7.415.1 6.4 16.2 11.6 17.0 7.1 19.1 13.3 21.1 20.7 22.3 7.2 22.9 11.9 26.25.8 29.6 4.4

The PXRD pattern corresponding to the Freebase Hydrate Form B is shownin FIG. 19. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 15-B below.

TABLE 15-B PXRD Peak Listing Freebase Hydrate Form B PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.1 100.0 6.1 3.4 7.9 4.6 9.3 54.8 10.7 3.1 12.0 27.112.4 6.3 13.0 3.3 13.7 4.3 14.9 7.5 15.6 4.2 16.0 3.5 17.1 3.7 18.8 7.020.8 13.4 22.9 6.6 23.3 4.5 24.0 6.6 24.6 4.2 25.0 12.4 26.0 4.7 26.95.1 28.1 3.3 28.9 2.5 29.8 4.1

The PXRD pattern corresponding to the Freebase Hydrate Form C is shownin FIG. 20. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 15-C below.

TABLE 15-C PXRD Peak Listing Freebase Hydrate Form C PEAK POSITION (°2Θ)RELATIVE INTENSITY 7.7 28.8 7.9 41.1 9.6 10.2 10.3 35.0 12.4 9.8 13.472.5 13.9 16.9 15.1 74.6 15.5 93.7 15.9 11.7 17.0 76.1 17.2 46.8 17.821.6 18.1 10.0 18.3 37.2 19.3 33.0 19.7 24.7 20.5 52.4 20.9 54.9 21.27.9 21.7 100.0 21.9 34.6 22.2 21.7 22.6 6.2 23.5 27.2 24.0 5.0 24.4 1824.9 35.1 27.4 9.8 28.2 19.8 29.2 8.2 29.5 13.7 31.5 6.9

The PXRD pattern corresponding to the Tartrate Hydrate is shown in FIG.21. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 15-D below. The experimental PXRD patternis shown at the bottom of FIG. 21 and the calculated PXRD pattern isshown at the top of FIG. 21.

TABLE 15-D PXRD Peak Listing Tartrate Hydrate PEAK POSITION (°2Θ)RELATIVE INTENSITY 3.9 80.3 6.8 24.6 10.4 12.8 11.8 21.6 14.1 100.0 15.763.3 16.1 10.4 17.1 4.5 18.0 22.1 18.4 11.6 18.8 12.4 19.7 5.2 20.0 3.121.2 15.2 21.9 55.9 24.0 11.9 24.8 3.0 25.2 3.6 25.9 32.6 26.7 9.2 27.06.8 27.6 11.5 28.7 6.3 30.4 4.9 30.9 4.9 32.4 4.3 33.4 3.0

The PXRD pattern corresponding to the Freebase Anhydrate Form D is shownin FIG. 22. Peak listing of the experimental PXRD pattern with relativeintensities is given in Table 15-E below.

TABLE 15-E PXRD Peak Listing Freebase Anhydrate Form D PEAK POSITION(°2Θ) RELATIVE INTENSITY 4.0 20.6 8.0 29.3 9.7 52.1 11.2 7.5 12.0 9.813.0 1.4 14.2 100.0 14.5 65.7 16.1 3.1 17.2 7.5 18.4 24.3 19.0 23.5 20.343.1 21.4 18.5 23.0 35.7 23.8 18.3 24.7 35.8 25.6 6.0 26.1 14.5 27.411.7 28.2 9.3 28.7 5.2 30.3 6.6 31.1 1.3 31.9 3.8 32.7 1.0 33.3 5.1 34.80.7

Example 8: Clinical Study for Crohn's Disease

This trial was a multicenter, randomized, double-blindplacebo-controlled study of upadacitinib for the induction ofsymptomatic and endoscopic remission in patient with moderately toseverely active Crohn's disease who have inadequately responded to orare intolerant to immunosuppressants or anti-TNF therapy.

The trial consisted of a screening period of up to 30 days, a 16 weekdouble blind induction period, re-randomization at week 16, a 36 weekdouble blind and open label phase and a 30 day follow up period.

Approximately 220 patients with moderately to severely active Crohn'sdisease—defined for purposes of this study as having 1) SimplifiedEndoscopic Score for CD (SES-CD)≥6, (or SES-CD≥4 for patients withdisease limited to the ileum), 2) a CDAI≥220 and ≤450, and 3) an averagedaily liquid/soft stool frequency (SF)≥2.5 or an average daily abdominalpain (AP) score ≥2.0)—were randomized in a 1:1:1:1:1:1 ratio to one ofthe schematics of the overall study design shown in FIG. 1.

-   -   1. Group 1: upadacitinib 3 mg BID capsules (IR)    -   2. Group 2: upadacitinib 6 mg BID capsules (IR)    -   3. Group 3: upadacitinib 12 mg BID capsules (IR)    -   4. Group 4: upadacitinib 24 mg BID capsules (IR)    -   5. Group 5: upadacitinib 24 mg QD dose (IR) (two 12 mg capsules        administered simultaneously)    -   6. Group 6: Placebo

The 16 week induction period began at the BL visit (week 0) and ended atthe week 16 visit. The randomization at BL was stratified by endoscopicdisease severity (SES-CD<15 and ≥15). Safety and efficacy evaluationswere performed through the end of the study. The end of the study wasdefined as the date the last patient completed the last follow up visit.

At week 16, patients who had completed the induction period werere-randomized to one of four double-blinded doses of upadacitinib: 3 mgBID, 6 mg BID, 12 mg BID, or 24 mg QD (patients administered two 12 mgcapsules simultaneously). The re-randomization was stratified by dosereceived during the first 16 weeks and overall response (responderversus non-responder) at week 16.

Each treatment group received the corresponding dose of upadacitinib orplacebo orally twice daily. Patients receiving the 24 mg QD dose wereadministered two 12 mg capsules simultaneously orally once daily. Atweek 12 and week 16, patients were evaluated for clinical remission(average daily SF≤1.5 and not worse than baseline and average dailyAP≤1.0 and not worse than baseline). Patients were randomly assigned(1:1) to have an endoscopy at either week 12 or at week 16, and wereevaluated for endoscopic remission (SES-CD≤4 and at least a two pointreduction in SES-CD versus BL and no subscore >1 in any individualvariable used to calculate SES-CD) at week 12 or week 16.

The central reader endoscopic score was used for calculating theendoscopic response for the evaluation of the efficacy endpoints.However, for stratification at the time of re-randomization, theendoscopic score at BL from central reader and the endoscopic score atweek 12 or week 16 from site local reader were used in order todetermine response status.

The co-primary endpoints for efficacy were:

-   -   endoscopic remission at week 12 or 16    -   clinical remission at week 16

Secondary endpoints to measure efficacy included:

-   -   CDAI<150 at week 16    -   decrease in CDAI of ≥70 points from BL at week 16    -   clinical remission at week 12    -   remission at week 16 (endoscopic remission at week 12 or 16 and        clinical remission at week 16)    -   response at week 16 (endoscopic response at week 12 or 16 and        clinical response at week 16)    -   endoscopic response at week 12 or 16    -   clinical response at week 16    -   whether a subject with an average daily SF≥2.5 and an average        daily AP score ≥2.0 at BL achieves clinical remission at week 16    -   whether a subject taking corticosteroids at BL who discontinues        corticosteroid use achieves CDAI<150 at week 16    -   whether a subject taking corticosteroids at BL who discontinues        corticosteroid use achieves endoscopic remission at week 12 or        week 16 and clinical remission at week 16    -   whether a subject taking corticosteroids at BL who discontinues        corticosteroid use achieves clinical remission at week 16    -   whether a subject taking corticosteroids at BL who discontinues        corticosteroid use achieves endoscopic remission at week 12 or        week 16    -   change from BL in fecal calprotectin level at week 16    -   change from BL in hs-CRP (high sensitivity C-reactive protein)        at week 16    -   change in the Inflammatory Bowel Disease Questionnaire (IBDQ)        from BL at week 16    -   whether a subject with isolated ileal Crohn's Disease achieves        remission at week 16    -   whether a subject achieves remission at week 52    -   whether a subject achieves endoscopic remission at week 52    -   whether a subject achieves clinical remission at week 52    -   whether a subject achieves response at week 52    -   endoscopic response at week 52    -   clinical response at week 52    -   whether a subject taking corticosteroids at BL who discontinued        corticosteroid use achieves CDAI<150 at week 52    -   whether a subject taking corticosteroids at BL who discontinued        corticosteroid use achieves remission at week 52    -   whether a subject taking corticosteroids at BL who discontinued        corticosteroid use achieves clinical remission at week 52    -   whether a subject taking corticosteroids at BL who discontinued        corticosteroid use achieves endoscopic remission at week 52    -   CDAI<150 at week 52    -   decrease in CDAI≥70 points from BL at week 52    -   change from BL in fecal calprotectin level at week 52    -   change from BL in hs-CRP at week 52    -   change in IBDQ from BL at week 52    -   whether subject with isolated ileal Crohn's Disease achieves        remission at week 52    -   change in extra-intestinal manifestations (EIMS) from BL at week        52

Methods

The study comprised two treatment periods: a 16 week double-blindinduction period and a 36 week double-blind extension phase. In theinduction period, patients with a diagnosis of ileal, colonic, orileocolonic Crohn's disease for ≥3 months prior to BL and confirmed byendoscopy during the screening period, a CDAI≥220 and ≤450, and who haveinadequately responded to or experienced intolerance to previoustreatment with an anti-TNF agent (e.g. infliximab, adalimumab orcertolizumab pegol), were assigned to receive one of the following dosesof upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD orplacebo. The co-primary endpoints were endoscopic remission at week 12or week 16 and clinical remission at week 16. Secondary endpointsincluded CDAI<150 at week 16 and endoscopic response at week 12 or 16.

Eligible patients were aged 18 to 75 years. They had a diagnosis of CDfor at least three months and at screening had moderate-to-severe CD,defined as a 1) SES-CD≥6 (or ≥4 for patients with disease limited to theileum), 2) a CDAI of 220-450, and 3) an average daily liquid/soft SFscore ≥2.5 or an average daily AP score ≥2.0. Patients had inadequatelyresponded to or experienced intolerance to previous treatment with ananti-TNF agent. Patients with a current diagnosis of ulcerative colitis,collagenous colitis or indeterminate colitis as well as patients withprevious exposure to a JAK inhibitor were excluded. See Table 16 belowfor key demographics and BL characteristics.

TABLE 16 Key Demographics and Baseline Characteristics Demographics andPBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD* Characteristics N =37 N = 39 N = 37 N = 36 N = 36 N = 35 Female, n (%) 24 (64.9) 19 (48.7)21 (56.8) 17 (47.2) 25 (69.4) 19 (54.3) Median Age, yrs 40.0 37.0 39.041.0 43.5 41.0 Disease duration, yrs 11.80 13.25 11.82 13.29 14.83 14.22CDAI, mean 288.4 298.0 316.1 305.1 294.3 315.1 SF, mean 5.85 5.63 7.386.45 5.64 6.73 AP score, mean 1.67 1.87 1.80 1.82 1.63 1.89 SES-CD, mean15.8 14.7 16.2 15.6 14.3 13.4 hsCRP, mean (mg/dL) 20.8 23.6 17.9 26.917.1 17.1 IBDQ, mean 118.0 115.2 113.7 115.2 113.8 120.7 Prioranti-TNFs, n (%)  0 2 (5.4) 2 (5.1) 1 (2.7) 2 (5.6) 0 2 (5.7)  1 15(40.5) 18 (46.2) 12 (32.4) 6 (16.7) 10 (27.8) 10 (28.6)  2 15 (40.5) 15(38.5) 20 (54.1) 24 (66.7) 15 (41.7) 16 (45.7)  3 5 (13.5) 4 (10.3) 4(10.8) 4 (11.1) 9 (25.0) 7 (20.0) ≥4 0 0 0 0 2 (5.6) 0 Steroid use atBL, n (%) 15 (40.5) 20 (51.3) 18 (48.6) 18 (50.0) 15 (41.7) 10 (28.6)Prior non-anti-TNF 14 (38) 15 (39) 19 (51) 15 (42) 16 (44) 14 (40)biologics (%) vedolilzumab, n (%) 10 (27) 12 (31) 14 (38) 15 (42) 12(33) 12 (34) *24 mg QD dose is two 12 mg doses given simultaneously

TABLE 17 Analysis of Primary Efficacy Endpoints PBO 3 mg BID 6 mg BID 12mg BID 24 mg BID 24 mg QD* N = 37 N = 39 N = 37 N = 36 N = 36 N = 35Endoscopic 0 (0.0%)  4 (10.3%) 3 (8.1%) 3 (8.3%)  8 (22.2%) 5 (14.3%)Remission¹ (week 12 or16) Risk Difference 10.3   8.1  8.3  22.2   14.3  P-value 0.056 0.108 0.099 0.004 0.025 94% CI  −(0.3, 201.) (−1.6, 16.4)(−1.5, 6.8) (6.8, 35.2)  (1.8, 25.5) Clinical Remission² 4 (10.8%) 5(12.8%) 10 (27.0%) 4 (11.1%) 8 (22.2%) 5 (14.3%) (week 16) Riskdifference 2.0  0.3  11.4   3.5  P-value 0.740 0.082 0.952 0.205 0.60795% CI (−12.3, 17.3) (−2.0, 34.3) (−14.1, 15.0) (−6.1, 28.5)  (−11.5,19.6) Note: Statistical significance was indicated by p value ≤ 0.10¹Endoscopic remission: SES-CD ≤ 4 and at least two point reduction inSES-CD versus BL and no subscore >1 in any individual variable ²clinicalremission: average daily liquid/very soft SF score ≤1.5 and not worsethan BL AND average daily AP score ≤1.0 and not worse than BL *24 mg QDdose is two 12 mg doses given simultaneously

TABLE 18 Analysis of Secondary Efficacy Endpoints (NRI) PBO 3 mg BID 6mg BID 12 mg BID 24 mg BID 24 mg QD^(&) N = 37 N = 39 N = 37 N = 36 N =36 N = 35 Week 16 Clinical Response¹ 12 (32.4%) 17 (43.6%) 21 (56.8%)*17 (47.2%) 22 (61.1%)* 17 (48.6%) Endoscopic Response 5 (13.5%) 9(23.1%) 16 (43.2%)* 14 (38.9%)* 18 (50.0%)* 17 (48.6%)* (weeks 12/16)²Clinical Remission and 0 1 (2.6%) 2 (5.4%) 1 (2.8%) 3 (8.3%)* 2 (5.7%)Endoscopic Remission Clinical and 1 (2.7%) 6 (15.4%)* 12 (32.4%)* 10(27.8%)* 14 (38.9%)* 12 (34.3%)* Endoscopic Response CDAI < 150 6(16.2%) 8 (20.5%) 11 (29.7%) 14 (38.9%)* 11 (30.6%) 7 (20.0%) CR100⁵ 10(27.0%) 13 (33.3%) 15 (40.5%) 16 (44.4%) 20 (55.6%)* 11 (31.4%) CR70⁶ 13(35.1%) 18 (46.2%) 20 (54.1%) 16 (44.4%) 23 (63.9%)* 17 (48.6%)Steroid-free 0/15 (0%) 0/20 (0)%) 1/18 (5.6%) 1/18 (5.6%) 2/15 (13.3%)0/10 (0%) remisison³ Steroid-free and 0/15 (0%) 4/20 (20.0%) 4/18(22.2%) 7/18 (38.9%)* 5/15 (33.3%)* 1/10 (10.0%) CDAI < 150³Steroid-free and 0/15 (0%) 5/20 (25%) 9/18 (50%) 8/18 (44%) 10/15 (67%)3/10 (30%) clinical response³ Week 12 Clinical Remission⁴ 4 (10.8%) 4(10.3%) 11 (29.7%)* 5 (13.9%) 9 (25.0%) 3 (8.6%) Clinical Response¹ 13(35.1%) 21 (53.8%) 24 (64.9%)* 19 (52.8%) 20 (55.6%) 18 (51.4%) CDAI <150 24.3% 18.4% 41.7%   47.2%* 38.9%  22.9% CR70⁶ 35.1% 38.5% 59.5%*47.2% 58.3%* 51.4% CR100⁵ 29.7% 30.8% 51.4%* 41.7% 52.8%* 40.0%*Statistical significance was indicated by p value ≤ 0.10 ^(&)24 mg QDdose is two 12 mg doses given simultaneously ¹Clinical response: averagedaily liquid/very soft SF score ≥30% reduction from BL and average dailyAP not greater than BL and/or average daily AP score ≥30% reduction fromBL and average daily liquid/very soft SF score not greater than BL²Endoscopic response: >25% decrease in SES-CD from BL, as scored bycentral reviewer ³Among subjects taking steroids at BL ⁴Clinicalremission: average daily liquid/very soft stool frequency score ≤1.5 andnot worse than BL AND average daily AP ≤ 1.0 and not worse than BL⁵Decrease in CDAI score ≥100 from baseline ⁶Decrease in CDAI score ≥70from baseline

TABLE 19 Analysis of Additional Efficacy Endpoints PBO 3 mg BID 6 mg BID12 mg BID 24 mg BID 24 mg QD** Endpoints^(&) N = 33 N = 38 N = 33 N = 34N = 30 N = 32 Modified Clinical 4 (12.1%) 6 (15.8%) 10 (30.3%)* 9(26.5%) 11 (36.7%)* 6(18.8%) Remission¹ (week 16) Endoscopic 1 (3.0%) 12.8% 18.9%* 27.8%* 36.1%* 25.7%* Improvement² (Week 12 or 16)^(&)Includes subjects with baseline SF ≥ 4.0 or AP ≥ 2.0. *Statisticalsignificance was indicated by p value ≤ 0.10. **24 mg QD dose is two 12mg doses given simultaneously ¹Clinical remission: average daily SF ≤2.8 and not greater than Baseline AND average daily AP ≤ 1.0 and notgreater than Baseline ²Endoscopic improvement: SES-CD > 50% reductionfrom BL or at least a 2 point reduction in SES-CD from BL or endoscopicremission

Results

Baseline demographics and disease characteristics were similar betweenstudy arms. In total there were 95 males and 125 females, with a meanage of 42.5 years and mean CDAI of 302.83; 96.0% percent of patients hadpreviously been exposed to ≥1 TNF antagonists. At week 12/16, endoscopicremission was achieved by 10.3%, 8.1%, 8.3%, 22.2% and 14.3% of patientstreated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD,respectively, of upadacitinib, compared with 0% of patients treated withplacebo (p=0.056, p=0.108, p=0.099, p=0.004, p=0.025, respectively, seeTable 17). At week 16, clinical remission was achieved by 12.8%, 27.0%,11.1%, 22.2% and 14.3% of patients treated with 3 mg BID, 6 mg BID, 12mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, compared10.8% of patients treated with placebo (p=0.740, p=0.082, p=0.952,p=0.205, p=0.607, respectively, see Table 17). Clinical remission wasobserved in some patients as early as week 12. The percentage ofpatients achieving clinical remission at week 12 is shown in FIG. 6A(patients not on baseline steroids) and FIG. 6B (patients who were onsteroids at baseline, and underwent mandatory taper of steroid dosestarting at week 2). The steroid taper consisted of a weekly decrease by5 mg/day of prednisone (or equivalent) for doses >10/mg/day ofprednisone (or equivalent) until a 10 mg/day (or equivalent) dose wasreached, then a weekly decrease by 2.5 mg/day (or equivalent) untildiscontinuation. Upadacitinib was shown to induce clinical remission asearly as week 12.

Clinical response was achieved at week 16 by 43.6%, 56.8%, 47.2%, 61.1%and 48.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mgBID and 24 mg QD, respectively, of upadacitinib, compared with 32.4% ofpatients treated with placebo. Endoscopic response was achieved at week12 or week 16 by 23.1%, 43.2%, 38.9%, 50.0% and 48.6% of patientstreated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD,respectively, of upadacitinib, compared with 13.5% of patients treatedwith placebo.

Clinical remission and endoscopic remission was achieved at week 16 by2.6%, 5.4%, 2.8%, 8.3% and 5.7% of patients treated with 3 mg BID, 6 mgBID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib,compared with 0% of patients treated with placebo. Clinical andendoscopic response was achieved at week 16 by 15.4%, 32.4%, 27.8%,38.9% and 34.3% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID,24 mg BID and 24 mg QD, respectively, of upadacitinib, compared with2.7% of patients treated with placebo. Results are shown in Table 18.

Clinical remission was achieved at week 12 by 10.3%, 29.7%, 13.9%, 25.0%and 8.6% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mgBID and 24 mg QD, respectively, of upadacitinib, compared with 10.8% ofpatients treated with placebo. Clinical response was achieved at week 12by 53.8%, 64.9%, 52.8%, 55.6% and 51.4% of patients treated with 3 mgBID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, ofupadacitinib, compared with 35.1% of patients treated with placebo.Results are shown in Table 18. The percentage of patients achievingclinical response at week 12 is shown in FIG. 6A (patients not onbaseline steroids) and FIG. 6B (patients who were on steroids atbaseline, and underwent mandatory taper of steroid dose starting at week2).

Modified clinical remission was achieved at week 16 by 15.8%, 30.3%,26.5%, 36.7%, and 18.8% of patients treated with 3 mg BID, 6 mg BID, 12mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, comparedwith 12.1% of patients treated with placebo. Results are shown in Table19.

Endoscopic improvement was achieved at week 12 or week 16 by 12.8%,18.9%, 27.8%, 36.1%, and 25.7% of patients treated with 3 mg BID, 6 mgBID, 12 mg BID, 24 mg BID and 24 mg QD, respectively, of upadacitinib,compared with 3.0% of patients treated with placebo. Results are shownin Table 19. Of the patients who were evaluated for endoscopicimprovement at week 12, 10.5%, 13.3%, 25%, 33.3%, and 12.5% of patientstreated with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg QD,respectively, of upadacitinib, achieved endoscopic improvement by week12, compared with 0% of patients treated with placebo. Of the patientswho were evaluated for endoscopic improvement at week 16, 15.8%, 27.8%,27.3%, 25%, and 31.3% of patients treated with 3 mg BID, 6 mg BID, 12 mgBID, 24 mg BID and 24 mg QD, respectively, of upadacitinib, achievedendoscopic improvement by week 16, compared with 6.7% of patientstreated with placebo. These results are shown in Table 20. These resultsshow that endoscopic improvement was observed as early as week 12.

By week 4 of the induction period, among Crohn's patients taperingcorticosteroids, 13.3%, 9.5%, 11.1%, 11.8%, 6.7% and 10% respectivelywere able to discontinue steroids with placebo, 3 mg BID, 6 mg BID, 12mg BID, 24 mg BID and 24 mg BID, respectively. By week 8 of theinduction period, among Crohn's patients tapering corticosteroids,26.7%, 23.8%, 44.4%, 64.7%, 53.3% and 40% respectively were able todiscontinue steroids 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mgBID, respectively. By week 12 of the induction period, among Crohn'spatients were able to discontinue steroids, 33.3%, 28.6%, 55.6%, 76.5%,60% and 40% respectively were able to reduce their steroid dose by ≥50%with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg BID,respectively. By week 16 of the induction period, among Crohn's patientstapering corticosteroids, 20%, 38.1%, 55.6%, 64.7%, 74.3% and 40%respectively were able to reduce their steroid dose by ≥50% withplacebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg BID,respectively.

By week 4 of the induction period, among Crohn's patients taperingcorticosteroids, 20%, 42.9%, 50%, 82.4%, 46.7% and 40% respectively wereable to reduce their steroid dose by ≥50% with placebo, 3 mg BID, 6 mgBID, 12 mg BID, 24 mg BID and 24 mg BID, respectively. By week 8 of theinduction period, among Crohn's patients tapering corticosteroids,55.3%, 42.9%, 66.7%, 88.2%, 66.7% and 60% respectively were able toreduce their steroid dose by ≥50% with placebo, 3 mg BID, 6 mg BID, 12mg BID, 24 mg BID and 24 mg BID, respectively. By week 12 of theinduction period, among Crohn's patients tapering corticosteroids,46.7%, 38.1%, 61.1%, 88.2%, 60% and 40% respectively were able to reducetheir steroid dose by ≥50% with placebo, 3 mg BID, 6 mg BID, 12 mg BID,24 mg BID and 24 mg BID, respectively. By week 16 of the inductionperiod, among Crohn's patients tapering corticosteroids, 33.3%, 38.1%,66.7%, 88.4%, 77.3% and 40% respectively were able to reduce theirsteroid dose by ≥50% with placebo, 3 mg BID, 6 mg BID, 12 mg BID, 24 mgBID and 24 mg BID, respectively.

At the end of the 16 week induction period, among Crohn's patients whodiscontinued corticosteroids, 11.1%, 5.9%, 20% and 10% achievedendoscopic remission with, 6 mg BID, 12 mg BID, 24 mg BID and 24 mg BID,respectively. At the end of the 16 week induction period, among patientswho discontinued corticosteroids, 6.7%, 4.8%, 16.7%, 17.6%, 20% and 20%achieved endoscopic response with placebo, 3 mg BID, 6 mg BID, 12 mgBID, 24 mg BID and 24 MG BID, respectively. At the end of the 16 weekinduction period, among patients who discontinued corticosteroids,14.3%, 22.2%, 11.8%, 33.3% and 10% achieved clinical remission with 3 mgBID, 6 mg BID, 12 mg BID, 24 mg BID and 24 MG BID, respectively. At theend of the 16 week induction period, among patients who discontinuedcorticosteroids 14.3%, 26.7%, 25.0%, 36.4% and 10% achieved modifiedclinical remission with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and 24MG BID, respectively. At the end of the 16 week induction period, amongpatients who discontinued corticosteroids 19.0%, 22.2%, 41.2%, 33.3% and10% achieved CDAI<150 with 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID and24 MG BID, respectively. The taper consisted of a weekly decrease by 5mg/day of prednisone (or equivalent) for doses >10/mg/day of prednisone(or equivalent) until a 10 mg/day (or equivalent) dose was reached, thena weekly decrease by 2.5 mg/day (or equivalent) until discontinuation.

TABLE 20 Analysis of Endoscopic Improvement by Week Evaluated PBO 3 mgBID 6 mg BID 12 mg BID 24 mg BID 24 mg QD Week 12 N = 18 N = 19 N = 15 N= 12 N = 18 N = 16 Endoscopic 0% 10.5%* 13.3% 25%* 33.3%* 12.5%Improvement PBO 3 mg BID 6 mg BID 12 mg BID 24 mg BID 24 mg QD Week 16 N= 15 N = 19 N = 18 N = 22 N = 12 N = 16 Endoscopic 6.7% 15.8% 27.8%27.3% 25% 31.3%* Improvement *Statistical significance was indicated byp value ≤ 0.10.

This study included refractory patients with moderately to severelyactive Crohn's disease, who have had Crohn's disease for more than tenyears and who have failed several treatments, including biologictreatments. Table 16 above shows the number of patients in the studythat received prior anti-TNF treatment, treatment with priornon-anti-TNF biologics, treatment with vedolilzumab, and who were beingtreated with steroids at baseline, as well as the average duration ofCrohn's disease at baseline. Typically, because refractory patients aretreated with different therapeutics, the efficacy of each treatmentprogressively decreases. Surprisingly, however, the current studydemonstrated that when treated with upadacitinib, the refractorypatients showed unprecedented efficacy. The results for refractorypatients in the study are shown in FIG. 9.

As shown by FIG. 9, refractory patients treated with upadacitinibachieved clinical remission and endoscopic response at unprecedentedrates. At week 16, 15.8% of refractory patients treated with 3 mg BID ofupadacitinib achieved clinical remission. At week 16, 30.3% ofrefractory patients treated with 6 mg BID of upadacitinib achievedclinical remission. At week 16, 26.5% of refractory patients treatedwith 12 mg BID of upadacitinib achieved clinical remission. At week 16,36.7% of refractory patients treated with 24 mg QD (two 12 mg BID dosesgiven simultaneously) achieved clinical remission.

In addition, as also shown in FIG. 9, a surprising proportion ofrefractory patients treated with upadacitinib achieved endoscopicremission at 12 or 16 weeks. 13.2% of refractory patients treated with 3mg BID of upadacitinib achieved endoscopic remission at 12 or 16 weeks.21.2% of refractory patients treated with 6 mg BID of upadacitinibachieved endoscopic remission at 12 or 16 weeks. 29.4% of refractorypatients treated with 2 mg BID of upadacitinib achieved endoscopicremission at 12 or 16 weeks. 33.3% of refractory patients treated with24 mg QD (two 12 mg doses given simultaneously) of upadacitinib achievedendoscopic remission at 12 or 16 weeks.

The relationship between upadacitinib plasma concentrations and theprimary endpoints and certain secondary and additional endpoints is setforth in FIGS. 3A-3I. Exposure-response relationships were observed forclinical response, clinical remission, CDAI remission (CDAI<150),endoscopic response, endoscopic improvement, and endoscopic remission.

Safety

The incident of adverse events was numerically higher (˜3-13%) inupadacitinib dose groups, compared to placebo, with no cleardose-relationship. Severe adverse events and treatment discontinuationsdue to adverse events were lower/comparable across all upadacitinib dosegroups compared to placebo except in the 12 mg BID dose group. Therewere no treatment emergent deaths in the study. Overall, the incidenceof adverse events of special interest were low (except for infections)and similar across all treatment groups. Infections were increased inall upadacitinib BID dose groups compared to placebo. Two adjudicatedmajor adverse cardiac events (MACE) were observed in the 12 mg BID dosegroup (two had an acute myocardial infarction).

The relationship between upadacitinib plasma concentration and thechange from baseline in hemoglobin levels, anemia, LDL and HDLcholesterol, neutropenia, lymphopenia, and natural killer (NK) celllevels was determined, and the results shown in FIGS. 5A-5H.Exposure-response relationships for effects of upadacitinib on NK cells,neutrophils, LDL and HDL cholesterol in Crohn's patients were generallyconsistent with those previously observed in RA patients. Compared to RApatients (data not shown), subjects with Crohn's had lower decreases inhemoglobin (FIG. 5A).

Example 9: Model Predicted Efficacy for Once-Daily Doses

Based on the data obtained in Example 8 for administration of animmediate release (IR) formulation of upadacitinib BID, theexposure-response relationships (simulating for 200 patients/arm) for 15mg, 30 mg, and 45 mg modified-release QD doses of upadacitinib, forplacebo, for 6 mg, 12 mg, 18 mg, and 24 mg IR BID doses of upadacitinib,and for 24 mg IR QD doses of upadacitinib was predicted. The fulltime-course for the different clinical endpoints was analyzed usingMarkov analyses. The Marko models allowed transition between response,no response, and dropouts. The models evaluated C_(p), C_(ave), C_(min),and C_(max) as predictors for drug efficacy. The different endoscopicendpoints at Week 12/16 were analyzed using logistic regressionanalyses. Then, the models were used to simulate clinical response,clinical remission, CDAI<150, endoscopic response, endoscopicimprovement and endoscopic remission at Weeks 12 and 16 (whenapplicable) for different dose regimens for both the immediate andmodified release formulation by back transforming exposures to doses.The results are set forth in FIGS. 4A-4F.

This modelling suggests 1-3% improvements in clinical parameters betweendoses with the MR formulation.

Example 10: Clinical Study for Crohn's Disease: Long-term Efficacy andSafety of Upadacitinib in Moderate to Severe Crohn's Disease

In Example 10, the extension phase of the Example 8 clinical study wasstudied and discussed. The trial was a multicenter, randomized,double-blind placebo-controlled study of upadacitinib for the inductionof symptomatic and endoscopic remission in patient with moderately toseverely active Crohn's disease who have inadequately responded to orare intolerant to immunosuppressants or anti-TNF therapy.

The trial consisted of a screening period of up to 30 days, a 16 weekdouble blind induction period, re-randomization at week 16, a 36 weekdouble blind and open label phase and a 30 day follow up period.

Approximately 220 patients with moderately to severely active Crohn'sdisease—defined for purposes of this study as having 1) SimplifiedEndoscopic Score for CD (SES-CD)≥6, (or SES-CD≥4 for patients withdisease limited to the ileum), 2) a CDAI≥220 and ≤450, and 3) an averagedaily liquid/soft stool frequency (SF)≥2.5 or an average daily abdominalpain (AP) score ≥2.0)—were randomized in a 1:1:1:1:1:1 ratio to one ofthe schematics of the overall study design shown in FIG. 1.

-   -   1. Group 1: upadacitinib 3 mg BID capsules (IR)    -   2. Group 2: upadacitinib 6 mg BID capsules (IR)    -   3. Group 3: upadacitinib 12 mg BID capsules (IR)    -   4. Group 4: upadacitinib 24 mg BID capsules (IR)    -   5. Group 5: upadacitinib 24 mg QD dose (IR) (two 12 mg capsules        administered simultaneously)

6. Group 6: Placebo

The 16 week induction period began at the BL visit (week 0) and ended atthe week 16 visit. The randomization at BL was stratified by endoscopicdisease severity (SES-CD<15 and ≥15). Safety and efficacy evaluationswere performed through the end of the study. The end of the study wasdefined as the date the last patient completed the last follow up visit.

At week 16, patients who completed the 16-week induction phases werere-randomised 1:1:1 to double-blind upadacitinib at 3 mg twice daily(BID), 12 mg BID or 24 mg daily (QD) for 36 weeks. A protocol amendmentstopped enrolment in the 24 mg QD arm and initiated a 6 mg BID arm. Atotal of 180 patients were re-randomised to one of four double-blindeddoses of upadacitinib:

-   -   1. Group 1: upadacitinib 3 mg BID capsules (IR)    -   2. Group 2: upadacitinib 6 mg BID capsules (IR)    -   3. Group 3: upadacitinib 12 mg BID capsules (IR)    -   4. Group 4: upadacitinib 24 mg QD dose (IR) (two 12 mg capsules        administered simultaneously)

The re-randomization was stratified by dose received during the first 16weeks and overall response (responder versus non-responder) at week 16.

Each treatment group received the corresponding dose of upadacitiniborally once or twice daily. Patients receiving the 24 mg QD dose wereadministered two 12 mg capsules simultaneously orally once daily. Atweek 52, patients were evaluated for clinical remission (average dailySF≤1.5 and not worse than baseline and average daily AP≤1.0 and notworse than baseline), CDAI<150, modified clinical remission (SF≤2.8 andAP≤1.0, both not worse than BL in patients with SF≥4, AP≥2.0 at BL),clinical response (≥30% decrease in SF or AP, both not worse than BL),endoscopic remission (SES-CD≤4 and ≥2-point reduction from BL and nosubscore >1), endoscopic response (SES-CD reduction >50% from BL orendoscopic remission) and change from BL in C-reactive protein (CRP) andfaecal calprotectin (FC).

The co-primary endpoints for efficacy were the same as the endpoints inExample 8 study.

Methods

The study comprised two treatment periods: a 16 week double-blindinduction period and a 36 week double-blind extension phase. In theinduction period, patients with a diagnosis of ileal, colonic, orileocolonic Crohn's disease for ≥3 months prior to BL and confirmed byendoscopy during the screening period, a CDAI≥220 and ≤450, and who haveinadequately responded to or experienced intolerance to previoustreatment with an anti-TNF agent (e.g. infliximab, adalimumab orcertolizumab pegol), were assigned to receive one of the following dosesof upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 24 mg BID or 24 mg QD orplacebo. The co-primary endpoints were endoscopic remission at week 12or week 16 and clinical remission at week 16. Secondary endpointsincluded CDAI<150 at week 16 and endoscopic response at week 12 or 16.In the extension phase, patients who completed the 16-week inductionphases were re-randomised 1:1:1 to double-blind upadacitinib at 3 mgtwice daily (BID), 12 mg BID or 24 mg daily (QD) for 36 weeks. Aprotocol amendment stopped enrolment in the 24 mg QD arm and initiated a6 mg BID arm. Clinical remission (average daily stool frequency [SF]≤1.5and abdominal pain score [AP] ≤1.0, both not worse than Baseline [BL]),CDAI<150, modified clinical remission (SF≤2.8 and AP≤1.0, both not worsethan BL in patients with SF≥4, AP≥2.0 at BL), clinical response (≥30%decrease in SF or AP, both not worse than BL), endoscopic remission(SES-CD≤4 and ≥2-point reduction from BL and no subscore >1), endoscopicresponse (SES-CD reduction >50% from BL or endoscopic remission) andchange from BL in C-reactive protein (CRP) and faecal calprotectin (FC)were analysed at week 52 in patients with either both clinical andendoscopic response or clinical response at week 16. Endoscopies wereevaluated at BL, 12/16 and 52 weeks by a central reader. Patients whoreceived open label upadacitinib (escape) or prematurely discontinuedprior to week 52 were considered non-responders (non-responderimputation). Adverse events were collected throughout the study up to 30days after the last upadacitinib dose.

Eligibility, key demographics and BL characteristics of the patientswere essentially the the same as those in Example 8 study.

TABLE 21 Analysis of Primary and Secondary Efficacy Endpoints (Clinicaland endoscopic endpoints at Week 52 in the CELEST study) 3 mg BID 6 mgBID 12 mg BID 24 mg QD^(&) Endpoint at Week 52 N = 32 N = 14 N = 29 N =19 Among subjects who achieved clinical response and endoscopic responseat Week 16 Modified clinical remission^(a), n (%) 7 (41.2)^(b) 5(62.5)^(b) 11 (73.3)^(b) 4 (40.0)^(b) Endoscopic response^(c), % 10(50.0)^(d) 4 (50.0)^(d) 11 (68.8)^(d) 3 (30.0)^(d) Among subjects whoachieved clinical response at Week 16 Modified clinical remission, n (%)8 (28.6)^(e) 6 (42.9)^(e) 14 (51.9)^(e) 7 (38.9)^(e) Endoscopicresponse, % 11 (34.4)^(f) 5 (35.7)^(f) 13 (44.8)^(f) 7 (36.8)^(f)Clinical remission^(g), n (%) 8 (25) 4 (29) 12 (41) 6 (32) CDAI < 150, %(n) 14 (44) 7 (50) 16 (55) 7 (37) Enhanced clinical response^(h), n (%)15 (47) 10 (71) 18 (62) 8 (42) Clinical response^(i), n (%) 16 (50) 10(71) 18 (62) 8 (42) Endoscopic remission^(j), n (%) 5 (16) 3 (21) 7 (24)5 (26) Mean change from BL in hs-CRP ± SD −2.8 ± 18.9 −2.1 ± 18.4 −13.9± 37.1 10.2 ± 55.7 Mean change from BL in FC ± SD   1.0 ± 2457.2 −239.3± 1443.1 −2617.4 ± 3232.0 −1510.3 ± 2773.9  ^(&)24 mg QD dose is two 12mg doses given simultaneously ^(a)Modified clinical remission: SF ≤ 2.8and AP ≤ 1.0, both not worse than BL in patients with SF ≥ 4 or AP ≥ 2.0at BL ^(b)For 3, 6, and 12 mg BID and 24 mg QD, n = 17, 8, 15. and 10^(c)Endoscopic response: SES-CD reduction >50% from BL or endoscopicremission, in responders and 28, 14, 27, and 18 in clinical responders,respectively ^(d)For 3, 6, and 12 mg BID and 24 mg QD, n = 20, 8, 16,and 10 ^(e)For 3, 6, and 12 mg BID and 24 mg QD, n = 28, 14, 27, and 18^(f)For 3, 6, and 12 mg BID and 24 mg QD, n = 32, 14, 29, and 19^(g)Clinical remission: SF ≤1.5 and AP ≤1.0 and both not worse than BL^(h)Enhanced clinical response: ≥60% reduction from induction BL in SFor ≥35% reduction from induction BL in AP and both not worse than BL ormodified clinical remission ^(i)Clinical response: ≥30% reduction fromBL in SF or ≥30% reduction from BL in AP and both not worse than BL.^(j)Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction fromBL and no subscore >1

Results

Baseline demographics and disease characteristics were similar betweenstudy arms. At week 52, endoscopic remission was achieved by 16%, 21%,24%, and 26% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID, and24 mg QD, respectively, of upadacitinib. At week 52, clinical remissionwas achieved by 25%, 29%, 41%, and 32% of patients treated with 3 mgBID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.Results are shown in Table 21.

Clinical response was achieved at week 52 by 50%, 71%, 62%, and 42% ofpatients treated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD,respectively, of upadacitinib Enhanced clinical response was achieved atweek 52 by 47%, 71%, 62%, and 42% of patients treated with 3 mg BID, 6mg BID, 12 mg BID and 24 mg QD, respectively, of upadacitinib. Resultsare shown in Table 21.

Among subjects who achieved clinical response and endoscopic response atweek 16, endoscopic response was achieved at week 52 by 50.0%, 50.0%,68.8%, and 30.0% of patients treated with 3 mg BID, 6 mg BID, 12 mg BID,and 24 mg QD, respectively, of upadacitinib. Among subjects who achievedclinical response at week 16, endoscopic response was achieved at week52 by 34.4%, 35.7%, 44.8%, and 36.8% of patients treated with 3 mg BID,6 mg BID, 12 mg BID, and 24 mg QD, respectively, of upadacitinib.Results are shown in Table 21. Among subjects who achieved clinicalresponse and endoscopic response at week 16, endoscopic response wasachieved at week 52 by 34.4, 35.7, 44.8 and 36.8% of patients treatedwith 3 mg BID, 6 mg BID, 12 mg BID and 24 mg QD, respectively.

Among subjects who achieved clinical response and endoscopic response atweek 16, modified clinical remission was achieved at week 52 by 41.2%,62.5%, 73.3%, and 40.0% of patients treated with 3 mg BID, 6 mg BID, 12mg BID, and 24 mg QD, respectively, of upadacitinib. Among subjects whoachieved clinical response at week 16, modified clinical remission wasachieved at week 52 by 28.6%, 42.9%, 51.9%, and 38.9% of patientstreated with 3 mg BID, 6 mg BID, 12 mg BID, and 24 mg QD, respectively,of upadacitinib. Results are shown in Table 21.

Safety

The incident of adverse events (AEs) was numerically higher withupadacitinib 3 and 12 mg BID (45 [75.0%] and 43 [72.9%]) than that with6 mg BID and 24 mg QD (14 [60.9%] and 23 [63.9%]), respectively. SeriousAEs were numerically higher with 3 mg BID and infections with 3 and 12mg BID than that in the other arms. Two malignancies occurred with 12 mgBID.

Conclusion

Dose-dependent improvements in clinical and endoscopic outcomes andmarkers of inflammation were observed with 36-week upadacitinibtreatment in patients who responded to a 16-week induction regimen. Theoverall safety profile of upadacitinib is consistent with other studiesin rheumatoid arthritis.

Example 11: Clinical Study for Crohn's Disease: Rapidity of Clinical andLaboratory Improvements Following Upadacitinib Induction Treatment

This analysis evaluates the rapidity of clinical remission, clinicalresponse, and changes in markers of inflammation during the inductionphase of the clinical study discussed in Example 8.

Methods

Adult patients with Crohn's Disease Activity Index (CDAI) 220-450,average daily liquid/very soft stool frequency (SF)≥2.5 or dailyabdominal pain score (AP)≥2.0, and Simplified Endoscopic Score for CD(SES-CD)≥6 [or ≥4 for those with isolated ileal disease), wererandomized to double-blind therapy with placebo (PBO) or immediaterelease formulation of upadacitinib at 3, 6, 12, 24 mg twice daily (BID)or 24 mg once daily (QD) for 16 weeks. Patients were randomized atbaseline for follow-up ileocolonoscopy at either Week 12 or 16.Proportion of patients with modified clinical remission and enhancedclinical response, both defined in Figure, mean change from baseline inC-reactive protein (CRP) and faecal calprotectin (FC) were assessed overtime in all patients unless otherwise mentioned. Comparisons betweeneach upadacitinib dose with PBO was tested by Cochran-Mantel-Haenszeltest stratified by SES-CD at BL. Non-responder imputation was applied topatients who received open-label upadacitinib or prematurelydiscontinued prior to Week 16 or initiated corticosteroids or had doseincrease higher than baseline.

Results

Baseline demographics and disease characteristics were similar betweenstudy arms. A total of 220 patients were enrolled (mean age 40.7±12.9years, CDAI 302.7±63.4, disease duration 13.2±10.0 years). Overall,patients receiving upadacitinib achieved modified clinical remission asearly as week 4 and enhanced clinical response at week 8. Over time,there were sustained clinical improvements in several upadacitinibdosage groups for up to 16 weeks (FIGS. 10A-10E and FIGS. 11A-11E). MeanC-reactive protein (CRP) levels significantly decreased in allupadacitinib doses at week 4 and were sustained for up to 16 weeks inthe 12 and 24 mg BID and 24 mg QD arms (FIG. 12). Statisticallysignificant decrease in mean faecal calprotectin (FC) from baseline wasobserved with upadacitinib at 12 and 24 mg BID at week 4 and 24 mg BIDat week 16.

Conclusions

Early and significant effects of upadacitinib in clinical parameterswere demonstrated in a refractory patient population with active Crohn'sdisease, concurrent with rapid and sustainable decrease in the markersof inflammation hsCRP and faecal calprotectin.

Example 12: Clinical Study for Ulcerative Colitis

This trial is a multicenter, randomized, double-blind placebo-controlledstudy of upadacitinib for the induction and maintenance of clinicalremission (using the Mayo Scoring System for Assessment of UlcerativeColitis Activity, excluding Physician's Global Assessment [i.e., AdaptedMayo score]) in patients with moderately to severely active ulcerativecolitis.

The trial consists of a screening period of up to 35 days, an 8 weekdouble blind induction period (Substudy 1), a second 8 week double blindand open label induction period (Substudy 2), re-randomization at week8, a 44 week double blind and open label maintenance phase (Substudy 3),and a 30 day follow up period.

Approximately 250 patients with moderately to severely active ulcerativecolitis are randomized in a 1:1:1:1:1 ratio for Substudy 1 to one of thetreatment arms of the overall study design shown in FIG. 13.

-   -   1. Group 1: upadacitinib 7.5 mg QD MR capsules    -   2. Group 2: upadacitinib 15 mg QD MRcapsules    -   3. Group 3: upadacitinib 30 mg QD MR capsules    -   4. Group 4: upadacitinib 45 mg QD MR capsules    -   5. Group 5: Placebo QD dose

The first 8 week induction period begins at the BL visit (week 0) andends at the week 8 visit. Once the 250 randomized patients havecompleted an 8 week induction, an analysis of efficacy and safety ofupadacitinib versus placebo will be performed. Based on this analysis,one induction dose of upadacitinib (Dose A) will be identified forfurther evaluation in Substudy 2. During the analysis period,approximately 100 additional subjects will continue to be randomizedinto Groups 3 and 4 of Substudy 1 to receive either 30 mg QD or 45 mg QDtreatment (50 patients per dose group).

Substudy 2 consists of two parts. In Part 1, approximately 375 patientswith moderately to severely active ulcerative colitis are randomized ina 2:1 ratio to one of the double-blinded induction treatment arms asshown in FIG. 13: upadacitinib Dose A mg QD or placebo QD. Dose A is thedose determined in Substudy 1 for further evaluation. Part 2 of Substudy2 is open label. Approximately 330 subjects will be enrolled in Part 2of Substudy 2 to receive open-label upadacitinib Dose A QD. This second8 week induction period begins at the BL visit (week 0) and ends at theweek 8 visit.

Approximately 450 patients who received the 15, 30 or 45 mg QD ofupadacitinib in Substudy 1 and those who received the selected inductiondose in Substudy 2 and who also achieved a clinical response (i.e., adecrease from baseline in the Adapted Mayo score ≥2 points and ≥30% frombaseline accompanied by a decrease in RBS≥1 or an absolute RBS≤1) willbe re-randomized in the maintenance portion of the study (Substudy 3).This period will begin at the baseline visit (Week 8 of Substudy 1 orSubstudy 2) and will end at the Week 44 visit. The treatment assignmentin Substudy 3 will depend on the treatment received in Substudies 1 and2, as follows:

Placebo: continue placebo

7.5 mg QD upadacitinib: continue 7.5 mg QD upadacitinib

15 mg QD upadacitinib: randomized 1:1 to receive either upadacitinib 15mg QD or matching placebo

30 mg QD or 45 mg QD upadacitinib: randomized 1:1:1 to receive eitherupadacitinib 15 mg QD, upadacitinib 30 mg QD, or matching placebo.

During Substudy 3, subjects who meet the criteria for loss of responseafter at least 4 weeks of follow up will have the option receive openlabel upadacitinib. Loss of response is defined as follows: a subjectwho presents with an stool frequency subscore and RBS score at least 1point greater than the end-of-induction value (Week 8 of Substudy 1 or2) on two consecutive visits at least 14 days apart. The schematics ofthe overall study design are shown in FIG. 13.

The primary endpoints for efficacy for Substudy 1 and Substudy 2 are theproportion of patients who achieve clinical remission per Adapted Mayoscore (defined as stool frequency subscore ≤1, rectal bleeding subscoreof 0, and endoscopic subscore ≤1) at week 8. The primary efficacyendpoint for Substudy 3 is the proportion of patients who achieveclinical remission per Adapted Mayo score at week 44. Secondary efficacyendpoints for both Substudy 1 and Substudy 2 are:

-   -   endoscopic improvement (defined as endoscopic subscore ≤1)    -   achieving Full Mayo score ≤2 with no subscore >1) at week 8    -   Clinical response (i.e., decrease from baseline in the Adapted        Mayo score ≥2 points and ≥30% from baseline, plus a decrease in        rectal bleeding subscore (RBS)≥1 or an absolute RBS≤1) at week 8    -   decrease from baseline in the Partial Mayo score ≥2 points and        ≥30% from baseline plus a decrease in rectal bleeding subscore        (RBS)≥1 or an absolute RBS≤1) at week 2    -   Change in Full Mayo score from Baseline to Week 8    -   Endoscopic remission (defined as endoscopic subscore of 0) at        Week 8    -   Histologic improvement (defined as decrease from baseline in        Geboes score) at week 8

Secondary efficacy endpoints for Substudy 3 maintenance are:

-   -   Endoscopic improvement at week 44    -   Full Mayo score ≤2 with no subscore >1) at week 44    -   Subjects who discontinued corticosteroid use and achieved        clinical remission per Adapted Mayo score at week 44    -   Subjects who maintain clinical remission at Week 44 among        subjects who achieved clinical remission per Adapted Mayo score        in Substudy 1 or 2    -   Subjects who are taking corticosteroids at baseline and are        corticosteroid-free at week 44    -   Subjects with endoscopic improvement at week 44 among subjects        who achieved clinical remission in Substudy 1 or 2    -   Subjects achieving clinical response (i.e., decrease from        baseline in the Adapted Mayo score ≥2 points and ≥30% from        baseline accompanied by a decrease in RBS≥1 or an absolute        RBS≤1) at week 44    -   Subjects with endoscopic remission at week 44    -   Subjects who achieved histologic improvement at week 44

Methods

The study comprised three treatment periods: Substudy 1 comprising an 8week double-blind induction period; Substudy 2 comprising two parts:Part 1 is an 8 week double-blind induction period and Part 2 is an 8week open-label option of the substudy; Substudy 3 evaluates patientsfrom Substudy 1 and Substudy 2 who achieved clinical response.

Eligible patients are aged 18 to 75 years. They have a diagnosis ofulcerative colitis for 90 days or greater prior to baseline, confirmedby colonoscopy during the screening period, with exclusion of currentinfection, colonic dysplasia and/or malignancy. Patients have activeulcerative colitis with an Adapted Mayo score of 5 to 9 points and anendoscopic subscore of 2 to 3 at baseline. Eligible patients are thosewho have demonstrated an inadequate response to or experiencedintolerance to corticosteroids, immunosuppressants and/or biologictherapies, as defined below:

-   -   Corticosteroids:        -   Signs and symptoms of persistently active disease despite a            history of at least one induction regimen that included a            dose equivalent to prednisone ≥40 mg/day orally for 3 to 4            weeks or intravenously for 1 week or        -   Unable to taper corticosteroids to below a doses equivalent            to prednisone 10 mg daily orally without recurrent active            disease or        -   History of intolerance to corticosteroids (including, but            not limited to Cushing's syndrome, osteopenia/osteoporosis,            hyperglycemia, insomnia, infection)    -   Immunosuppressants:    -   Signs and symptoms of persistently active disease despite a        history of at least one 90-day regimen of oral azathioprine        (≥1.5 mg/kg/day; for subjects in Japan and China only: ≥1.0        mg/kg/day), 6-mercaptopurine (≥1 mg/kg/day; for subjects in        Japan and China only: ≥0.6 mg/kg/day) or a documents 6-TGN level        of 230-450 pmol/8×10⁸ RBC or higher on the current dosing        regimen), injectable methotrexate (MTX≥15 mg/week subcutaneously        or intramuscular), or tacrolimus or        -   History of intolerance to at least one immunosuppressant            (including, but not limited to nausea/vomiting, abdominal            pain, pancreatitis, liver enzyme abnormalities, lymphopenia,            infection)    -   Biologic agents for UC:        -   Signs and symptoms of persistently active disease despite a            history of any of the following:            -   At least one 6-week induction regimen of infliximab (≥5                mg/kg intravenous at 0, 2 and 6 weeks),            -   At least one 4-week induction regimen of adalimumab (one                160 mg subcutaneous dose followed by 80 mg subcutaneous                dose [or one 80 mg subcutaneous dose) followed by one 40                mg subcutaneous dose at least 2 weeks apart),            -   At least one 2-week induction regimen of golimumab (one                200 mg subcutaneous dose followed by one 100 mg                subcutaneous dose at least two weeks apart),            -   At least one 6-week induction regimen of vedolizumab                (300 mg intravenous at 0, 2 and 6 weeks), or        -   Recurrence of symptoms during scheduled maintenance dosing            following prior clinical benefit (discontinuation despite            clinical benefit does not qualify) or        -   History of intolerance to at least one biologic agent            (including, but not limited to infusion-related reaction,            demyelination, congestive heart failure CHF), infection)

Oral MTX use is allowed during the study, however prior or current useof oral MTX is not sufficient for inclusion into the study unless thesesubjects were previously treated with corticosteroids orimmunosuppressants (azathioprine or 6-MP) and in the judgment of theinvestigator have failed to respond to or could not tolerate theirtreatment.

Examples 13-16: Modified Release Tablets

Modified release tablets containing either 7.5 mg (Example 13) 15 mg(Example 14), 30 mg (Example 15), or 45 mg (Example 16) of upadacitinibwere prepared using a wet granulation process.

Upadacitinib (hemi-hydrate), microcrystalline cellulose (MCC), andhydroxypropyl methylcellulose (HPMC) were added to a granulator andmixed. Water was sprayed to granulate. The granulated material was thendried and milled using a comill fitted with a 610 micron screen to forma granulate composition containing 25% drug load. The granulatecomposition is summarized in Table 22.

TABLE 22 Granulate Composition (25% Drug Load) Amount in GranulationComponent Function Composition (%) Upadacitinib freebase (hemi- Active25.0% hydrate)¹ Microcrystalline cellulose Filler 67.0% (Avicel ® PH101) HPMC (Hypromellose 2208) Release control 8.0% polymer ¹Upadacitinibused in Examples 13-16 was a hemi-hydrate (Freebase Hydrate Form C, asdescribed herein and in U.S. Patent Application No. 15/295,561). As usedherein, the amount of upadacitinib present in the Examples 13-16formulations refers to the amount of upadacitinib freebase equivalentprovided by the hemi-hydrate.

The granulation composition was combined with the remaining formulationcomponents other than magnesium stearate, and sieved using a comillfitted with a 1397 micron screen, followed by blending. The magnesiumstearate was then added to the bin and blended. The lubricatedgranulation was compressed into tablets using a rotary tablet press. Thetablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until thedesired amount of coating had been applied to the tablets.

The formulations of the tablets are set forth in Table 23.

TABLE 23 Modified Release Tablets Ex. 13 Ex. 14 Ex. 15 Ex. 16 ComponentFunction (mg) (mg) (mg) (mg) Tablet Core Granulation composition Active30.7¹ 61.4² 122.8³ 184.3⁴ (25% drag load) Microcrystalline celluloseFiller 149.5 121.3 64.8 8.3 (Avicel ® PH 102) Mannitol (Pearlitol ®Filler 100.6 100.6 100.6 100.6 100SD) Tartaric acid (crystalline pH 96.096.0 96.0 96.0 or powder) modifier HPMC (Hypromellose Release control93.5 91.1 96.2 81.3 2208) polymer Colloidal silicon dioxide Glidant 2.42.4 2.4 2.4 Magnesium stearate Lubricant 7.2 7.2 7.2 7.2 Uncoated weightof tablet 479.9 480.0 480.0 480.1 Opadry ® II Yellow Film coat 14.4 14.414.4 14.4 Purified Water⁵ Processing aid n/a n/a n/a n/a Total weight oftablet 494.3 494.4 494.4 494.5 ¹Provides 7.5 mg of upadacitinib freebaseequivalent. ²Provides 15 mg of upadacitinib freebase equivalent.³Provides 30 mg of upadacitinib freebase equivalent. ⁴Provides 45 mg ofupadacitinib freebase equivalent. ⁵Processing aid removed duringcoating.

Example 17: Observed Steady State Exposures for 15 mg Modified ReleaseTablets and 6 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of a 15 mg once daily modifiedrelease (MR) tablet (comprising upadacitinib hemi-hydrate) under fastingconditions was evaluated, and compared to that of a 6 mg immediaterelease (IR) twice daily (BID) capsule comprising upadacitinib (tartratetetrahydrate) as the active. The 15 mg MR tablet had the followingformulation set forth in Table 24.

TABLE 24 15 mg Modified Release Tablet Amount Component Function (mg)(ER7) Upadacitinib (hemi-hydrate)¹ Active 15.4 Microcrystallinecellulose Filler 162.4 (Avicel ® PH 102) Mannitol (Pearlitol ® 100 SD)Filler 52.6 Tartaric acid pH modifier 144.0 HPMC (Hypromellose 2208)Release 96.0 control polymer Colloidal silicon dioxide Glidant 2.4Magnesium stearate Lubricant 7.2 impalpable powder Uncoated weight oftablet 480.0 Opadry ® II Yellow Film coat 14.40 (PVA based) Total weightof tablet 494.39 ¹Upadacitinib was a hemi-hydrate (Freebase Hydrate FormC. as described herein and in U.S. Patent Application No. 15/295,561).The hemi-hydrate provides about 15 mg of upadacitinib freebaseequivalent.

The tablet was prepared by first milling the tartaric acid through aFitz mill Model MSA, fitted with a 1512-0027 screen. The upadacitinibhemi-hydrate, microcrystalline cellulose, mannitol (when present),milled tartaric acid, release control polymer, and colloidal siliconedioxide (when present) were combined and blended. The blend was milledusing a Mobil Mill fitted with a 610 or 1397 micron screen. Themagnesium stearate was screened through mesh #30 and was then added tothe bin and blended. The lubricated granulation was compressed intoabout 480 mg weight tablets using a rotary tablet press. The tablet wascoated using a film coater, which sprayed a solution containing theOpadry® II Yellow film coat and purified water until 14.40 mg of coatinghad been applied to the tablets.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen K (n=12 at onset; n=11 on Day 7) were administeredthe 6 mg IR capsule twice daily for seven days under fasting conditions.Subjects in Regimen L (n=12) were administered the 15 mg MR tablet oncedaily for seven days under fasting conditions. On days one and seven,serial blood samples were collected from each subject prior to the dailydosing and up to 24 hours after dosing. Blood samples were alsocollected at 48, 72, 96 and 120 hours after initial dosing. Uponcollection, the samples were promptly placed in an ice bath, and within2 hours after sample collection they were centrifuged at about 4° C. Theresulting plasma samples were placed in clean polypropylene-tubes andstored in a freezer until analysis. The plasma samples were assayed forupadacitinib using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 25. The mean plasma concentration ofupadacitinib at each time point measured for each of the two regimens isset forth in FIG. 7.

TABLE 25 Mean (% CV)^(e) Pharmacokinetic Parameters for UpadacitinibFollowing Administration of 6 mg BID (IR) Capsules and 15 mg QD (MR)Tablets for Seven Days (Fasting Conditions) Regimen K Regimen L (6 mg IRCapsules (BID)) (15 mg MR Tablet (QD)) PK Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 36.5 (25) 33.9 (26) 31.7 (40) 31.9 (35)T_(max) ^(a) hours 1.0 (1.0-13) 1.0 (0.5-14) 3.0 (1.5-6.0) 2.5 (1.5-4.0)AUC₂₄ ng · h/mL 289 (21) 288 (22) 249 (29) 279 (26) C₁₂ ng/mL 2.0 (30)2.8 (24) — — C₂₄ ng/mL 3.2 (36) 3.6 (23) 1.9 (42) 3.1 (37) C_(min) ng/mL— 2.7 (26) — 3.1 (37) Fluctuation Index % 303 (13) 259 (13) 299 (22) 246(21) t_(1/2) ^(b) hours — 14.7 (77) — 10.3 (76) C_(max) to C₂₄ ratio^(a)— 12 (7.7-19) 8.8 (7.4-13) 22 (5.8-43) 12 (4.2-20) C_(max) to C_(min)ratio^(a) — — 13 (8.3-18) — 12 (4.2-20) AUC₂₄/Dose (ng · h/mL)/mg 24.8(23) 24.0 (22) 16.6 (29) 18.6 (26) R_(AUC) ^(c) — — 1.02 (0.88-1.09) —1.11 (0.87-1.99) R_(Cmax) ^(d) — — 0.97 (0.68-1.17) — 1.01 (0.65-3.01)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for the once-daily (MR) tablet formulation(Regimen L) relative to the twice daily (IR) capsule formulation(Regimen K) at steady state was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 26 below.

TABLE 265 Relative Bioavailability Estimates and 90% ConfidenceIntervals for 15 mg QD Tablets Relative to 6 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability 90% ConfidencePK Parameter Point Estimate Interval C_(max) 0.909 0.736-1.122 AUC₂₄0.939 0.837-1.053 C_(min) 1.090 0.852-1.395

The ratio of steady-state AUC for the 15 mg QD tablets relative to the 6mg BID capsules was approximately 1, with the 90% confidence intervalswithin the equivalence boundaries. The ratio of the steady-state C_(min)was approximately 1 for the 15 mg QD tablet relative to the 6 mg BIDcapsules.

As can be seen from this data, at steady state under fasting conditions,the 15 mg QD tablets provided equivalent AUC₂₄ and comparable C_(max)and C_(min) relative to the 6 mg BID capsules. The steady state C_(max)was 10% lower for the 15 mg QD tablet compared to the 6 mg BID capsule.

Example 18: Observed Steady State Exposures for 30 mg Modified ReleaseTablets and 12 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of a 30 mg once daily modifiedrelease (MR) tablet (comprising upadacitinib hemi-hydrate) under fastingconditions was evaluated, and compared to that of a 12 mg immediaterelease (IR) twice daily (BID) capsule comprising upadacitinib (tartratetetrahydrate) as the active. The 30 mg MR tablet had the followingformulation set forth in Table 27.

TABLE 27 30 mg Modified Release Tablet Amount Component Function (mg)(ER8) Upadacitinib (hemi-hydrate)¹ Active 30.7 Microcrystallinecellulose Filler 147.1 (Avicel ® PH 102) Mannitol (Pearlitol ® 100 SD)Filler 52.6 Tartaric acid pH modifier 144.0 HPMC (Hypromellose 2208)Release control polymer 96.0 Colloidal silicon dioxide Glidant 2.4Magnesium stearate Lubricant 7.2 impalpable powder Uncoated weight oftablet 480.0 Opadry ® II Yellow (PVA Film coat 14.40 based) Total weightof tablet 494.43 ¹Upadacitinib was a hemi-hydrate (Freebase Hydrate FormC, as described in U.S. Patent Application No. 15/295,561). Thehemi-hydrate provides about 30 mg of upadacitinib freebase equivalent.

The tablet was prepared by first milling the tartaric acid through aFitz mill Model MSA, fitted with a 1512-0027 screen. The upadacitinibhemi-hydrate, microcrystalline cellulose, mannitol (when present),milled tartaric acid, release control polymer, and colloidal siliconedioxide (when present) were combined and blended. The blend was milledusing a Mobil Mill fitted with a 610 or 1397 micron screen. Themagnesium stearate was screened through mesh #30 and was then added tothe bin and blended. The lubricated granulation was compressed intoabout 480 mg weight tablets using a rotary tablet press. The tablet wascoated using a film coater, which sprayed a solution containing theOpadry® II Yellow film coat and purified water until 14.40 mg of coatinghad been applied to the tablets.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen M (n=11) were administered the 12 mg IR capsuletwice daily for seven days under fasting conditions. Subjects in RegimenN (n=12 at onset; n=11 at Day 7) were administered the 30 mg MR tabletonce daily for seven days under fasting conditions. On days one andseven, serial blood samples were collected from each subject prior tothe daily dosing and up to 24 hours after dosing. Blood samples werealso collected at 48, 72, 96 and 120 hours after initial dosing. Uponcollection, the samples were promptly placed in an ice bath, and within2 hours after sample collection they were centrifuged at about 4° C. Theresulting plasma samples were placed in clean polypropylene-tubes andstored in a freezer until analysis. The plasma samples were assayed forupadacitinib using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 28. The mean plasma concentration ofupadacitinib at each time point measured for each of the two regimens isset forth in FIG. 8.

TABLE 28 Mean (% CV)^(e) Pharmacokinetic Parameters for UpadacitinibFollowing Administration of 12 mg BID (IR) Capsules and 30 mg QD (MR)Tablets for Seven Days (Fasting Conditions) Regimen M Regimen N (12 mgIR Capsules (BID)) (30 mg MR Tablet (QD)) PK Parameter Units Day 1 Day 7Day 1 Day 7 ng/mL 80.8 (23) 73.9 (19) 65.7 (22) 68.2 (30) T_(max) ^(a)hours 1.0 (0.5-13) 1.0 (0.5-1.5) 2.5 (1.5-4.0) 3.0 (2.0-4.0) AUC₂₄ ng ·h/mL 497 (15) 534 (18) 454 (23) 525 (23) C₁₂ ng/mL 3.0 (46) 4.1 (55) — —C₂₄ ng/mL 6.5 (54) 6.9 (37) 2.8 (37) 4.4 (39) C_(min) ng/mL — 3.8 (58) —3.8 (43) Fluctuation Index % 388 (15) 317 (14) 349 (12) 291 (17) t_(1/2)^(b) hours — 7.3 (60) — 14.4 (64) C_(max) to C₂₄ ratio^(a) — 15 (5.4-20)12 (5.9-16) 29 (13-38) 17 (4.1-33) C_(max) to C_(min) ratio^(a) — — 19(8.4-31) — 17 (11-37) AUC₂₄/Dose (ng · h/mL)/mg 21.1 (15) 22.3 (18) 15.1(22) 17.5 (23) R_(AUC) ^(c) — — 1.08 (0.97-1.18) — 1.11 (0.79-1.67)R_(Cmax) ^(d) — — 0.98 (0.65-1.18) — 1.03 (0.40-1.82) ^(a)Median(minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC) = AUC₂₄Day7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day 7/C_(max)Day 1;median (range) ^(e)Data in parentheses is the coefficient of variance ofthe PK parameter (% CV), unless otherwise indicated

The relative bioavailability for a single dose of the once-daily (MR)tablet formulation (Regimen N) relative to the twice daily (IR) capsuleformulation (Regimen M) was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 29 below.

TABLE 29 Relative Bioavailability Estimates and 90% Confidence Intervalsfor 30 mg QD Tablets Relative to 12 mg BID Capsules at Steady Stateunder Fasting Conditions Relative Bioavailability 90% Confidence PKParameter Point Estimate Interval C_(max) 0.900 0.732-1.107 AUC₂₄ 0.9740.869-1.092 C_(min) 0.874 0.747-1.022

The ratio of steady-state AUC for the 30 mg QD tablets relative to the12 mg BID capsules was approximately 1, with the 90% confidenceintervals within the equivalence boundaries. The steady-state C_(min)for the 30 mg QD tablet was approximately 13% lower than for the 12 mgBID capsules. Outliers with high C_(min) in the 12 mg BID dose may havecontributed to this difference.

As can be seen from this data, at steady state under fasting conditions,the 30 mg QD tablets provided equivalent AUC₂₄ and comparable C_(max)and C_(min) relative to the 12 mg BID capsules. The steady state C_(max)was 10% lower for the 30 mg QD tablet compared to the 12 mg BIDcapsules.

Example 19. Clinical Study for Ulcerative Colitis

This study is a Phase 3, multicenter, randomized, double-blind,placebo-controlled efficacy and safety study to evaluate the efficacyand safety of upadacitinib (ABT-494) in subjects with moderately toseverely active ulcerative colitis.

Objective

The primary objective of this study is to evaluate the efficacy andsafety of upadacitinib 45 mg once daily (QD) compared to placebo ininducing clinical remission (per Adapted Mayo score) in subjects withmoderately to severely active ulcerative colitis (UC). Particularly, theprimary objective is to evaluate the efficacy and safety of upadacitinib45 mg once daily (QD) compared to placebo in inducing clinical remission(per Adapted Mayo score) in subjects with moderately to severely activeUC who have demonstrated inadequate response, loss of response, orintolerance to oral aminosalicylates, immunosuppressants,corticosteroids, and/or biologic therapies.

The secondary objectives of the study are to evaluate the efficacy ofupadacitinib 45 mg QD comparing with placebo in ranked secondaryendpoints of achieving endoscopic improvement, endoscopic remission,clinical response per Adapted Mayo Score, clinical response per PartialAdapted Mayo score, histologic-endoscopic mucosal improvement, no bowelurgency, no abdominal pain, histologic improvement, mucosal healing, andchange in IBDQ total score and FACIT-F score.

The study will allow enrollment of up to 30% of enrolled bio-IR subjectswho have failed 3 or more biologics. Among non-bio-IR subjects, subjectswho have used a biologic up to 1 year and have discontinued for reasonsother than inadequate response, loss of response, or intolerance (e.g.,change of insurance/reimbursement, well-controlled disease, etc.) may beenrolled but must meet other criteria for inadequate response, loss ofresponse, or intolerance to aminosalicylates, corticosteroids, orimmunosuppressants as defined in the protocol. The study will allow forenrollment of up to 20% enrolled non-bio-IR subjects who could also haveprevious use of a biologic therapy but discontinued based on reasonsother than inadequate response, loss of response, or intolerance. Thestudy will also evaluate the efficacy of an additional 8-weekupadacitinib 45 mg QD treatment in subjects who did not achieve clinicalresponse in the initial 8-week induction phase.

Study Population:

Males and females between 18 and 75 years of age with a diagnosis ofmoderately to severely active UC. Adolescent males and females 16 and 17years of age with body weight ≥40 kg and meet the definition of TannerStage 5 will be enrolled if approved by the country or regulatory/healthauthority. If these approvals have not been granted, only subjects ≥18years old will be enrolled. The study will consist of a mixedpopulation: biologic-inadequate responders (bio-IR) andnon-biologic-inadequate responders (non-bio-IR). The number of enrollednon-biologic-inadequate responders (non-bio-IR) subjects will be atleast 25% and not exceed 50%.

This study will allow enrollment of up to 30% of enrolled bio-IRsubjects who have failed 3 or more biologics. Among non-bio-IR subjects,subjects who have used a biologic up to 1 year and have discontinued forreasons other than inadequate response, loss of response, or intolerance(e.g., change of insurance/reimbursement, well-controlled disease, etc.)may be enrolled but must meet other criteria for inadequate response,loss of response, or intolerance to aminosalicylates, corticosteroids,or immunosuppressants as defined in the protocol. The study will allowfor enrollment of up to 20% enrolled non-bio-IR subjects who could alsohave previous use of biologic therapy but discontinued based on reasonsother than inadequate response, loss of response, or intolerance.

The study duration could be up to 25 weeks (excluding a possible washoutperiod), including a Screening Period of up to 5 weeks, an 8-weekdouble-blind Induction Period, an 8-week Open Label Extended TreatmentPeriod (for eligible subjects), and a 30-day Follow-Up Period, if thesubject does not meet eligibility to proceed to Study M14-234 Substudy3.

Number of Subjects to be Enrolled:

A total of approximately 462 subjects will be enrolled worldwide. Thenumber of non-bio-IR subjects enrolled will be at least 25% and notexceed 50% of the total number of subjects enrolled.

Methodology:

At the end of either Week 8 (Part 1) or Week 16 (Part 2), if subjectsare eligible, they will be offered an opportunity to participate inStudy M14-234 Substudy 3 which is a Phase 3 study designed to evaluatethe efficacy and safety of oral administration of upadacitinib 15 mg or30 mg compared to placebo as maintenance therapy in subjects withmoderately to severely active UC who achieved clinical responsefollowing induction with upadacitinib in Study M14-675.

Subjects who consent and meet all of the inclusion criteria and none ofthe exclusion criteria will be enrolled into Study M14-675, whichconsists of two parts: (Part 1) a randomized, double-blind,placebo-controlled 8-week induction study; and (Part 2) an 8-weekExtended Treatment Period for clinical non-responders from Part 1.

Part 1

In Part 1, approximately 462 subjects will be randomized in a 2:1 ratioto double-blind upadacitinib 45 mg QD or matching placebo for 8 weeks.The randomization will be stratified by bio-IR status (bio-IR vsnon-bio-IR), corticosteroid use (yes or no) and Adapted Mayo score (≤7or >7) at Baseline. Within bio-IR, the randomization will be furtherstratified by number of prior biologic treatments (≤1 or >1). Withinnon-bio-IR, the randomization will be further stratified by previousbiologic use (yes or no).

Treatment groups for Part 1 include:

-   -   Group 1: Upadacitinib 45 mg QD (blinded, n=308)    -   Group 2: Placebo QD (blinded, n=154)

At Week 8, subjects achieving clinical response, defined as a decreasefrom Baseline in the Adapted Mayo score ≥2 points and ≥30% fromBaseline, PLUS a decrease in rectal bleeding subscore (RBS)≥1 or anabsolute RBS≤1 may be eligible to enter the 52-week, double-blind,maintenance portion of Study M14-234 (Substudy 3).

All subjects who do not achieve clinical response at Week 8 will beeligible to participate in Part 2 (Extended Treatment Period) to receiveopen-label upadacitinib 45 mg QD for an additional 8 weeks.

Part 2

Part 2 is an open-label, 8-week Extended Treatment Period for subjectswho do not achieve clinical response at Week 8 in Part 1. The objectivesof Part 2 are to offer upadacitinib induction treatment to placeboclinical non-responders from Part 1 and to evaluate delayed clinicalresponse of upadacitinib in subjects who do not initially respond duringPart 1. The blind from Part 1 will not be broken for the duration of thestudy as subjects will be assessed as clinical non-responders at the 8Week Visit of Part 1 and will be moved to Part 2 for further treatmentin the study without identifying their initial treatment assignment. Alleligible subjects entering Part 2 will receive open-label treatment withupadacitinib 45 mg QD for 8 additional weeks (until Week 16). At Week16, an endoscopy will be performed to evaluate the treatment effect. Aflexible rectosigmoidoscopy is recommended. However, the use of flexiblesigmoidoscopy or colonoscopy is at the investigators' discretion basedon local practice.

During Part 2, subject with persistent symptoms or worsening UC may bediscontinued at any time. At Week 16, subjects who achieve clinicalresponse may be eligible to enter Study M14-234 (Substudy 3) for furtherblinded treatment. Subjects who do not achieve clinical response at Week16 will be discontinued from the study and will not be eligible toenroll in Study M14-533 (long term extension)

All subjects will be provided with a Subject Diary (eDiary) at Screeningin Study M14-675 where they will record UC-related symptoms, use ofanti-diarrheals, and use of medications for endoscopy preparation. Forthe assessment of the clinical endpoints, the stool frequency and therectal bleeding subscore will be calculated as an average of the entriesrecorded into the subject's diary from the most recent consecutive 3-dayperiod prior to each study visit. If diary entries from the 3consecutive days prior to the visit are not available, the 3 most recentconsecutive days in the last 10 days will be utilized. If data is notavailable for 3 consecutive days, the average of the entries from themost recent 3 non-consecutive days in the last 10 days will be utilized.Clinical endpoints of abdominal pain and bowel urgency from subjectdiaries will be measured at the same time period as the stool frequencyand rectal bleeding subscores. Proportion of subjects who report noabdominal pain and proportion of subjects who report no bowel urgency inthe 3 days will be estimated.

At each study visit, a routine physical examination including evaluationof vital signs, evaluation of extra-intestinal manifestations (EIMs),diary review, monitoring for adverse events (AEs), review of concomitantmedications, and completion of laboratory assessments will be performed.A full physical examination will be performed at Screening, Baseline,Week 8 and Week 16/Premature Discontinuation (PD) (for subjects whoenter the Extended Treatment Period) and must include an evaluation ofextra-intestinal manifestations. Symptom based physical examinationswill be performed at all other visits at a minimum, but evaluation ofEIMs will still be completed at every study visit.

Subjects will undergo a full colonoscopy with biopsy for histologicassessment during Screening with local investigator assessment for Mayoendoscopic subscore for initial eligibility assessment, confirmed by acentral reader prior to randomization. At end of treatment (Week 8 inPart 1) a full colonoscopy or flexible sigmoidoscopy, depending on theextent of disease at Screening, will be performed.

For subjects in Part 2, an endoscopy will be performed at Week 16/PD. Aflexible rectosigmoidoscopy is recommended at Week 16/PD, however, theuse of flexible rectosigmoidoscopy or colonoscopy will be based on theinvestigator's discretion per local practice.

The endoscopic subscore result from the central reader during thescreening period will be used to evaluate the eligibility of a subjectto enroll in the study and for all efficacy assessments at Week 8 ofPart 1. However, for re randomization into Substudy 3, the endoscopicsubscore at Week 8 (Study M14 675 Part 1) or Week 16 (Study M14-675 Part2) based on the local reader's assessment will be used to determineclinical response status compared to the Baseline assessment of thecentral reader for enrollment into Study M14-234 Substudy 3.

In addition to the Mayo endoscopic subscore, the central reader willassess the endoscopy findings using the Ulcerative Colitis EndoscopicIndex of Severity (UCEIS) scoring system for additional exploratoryanalyses. Blood samples will be collected for high sensitivityC-reactive protein (hs-CRP), upadacitinib plasma concentrations andother biomarker analyses. In addition, stool samples for fecalcalprotectin will be collected. The stool samples should be taken beforestarting bowel preparations for scheduled endoscopies.

Subjects will be asked to fill out the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), Work Productivity and Activity Impairment (WPAI),European Quality of Life 5 Dimensions 5 Levels (EQ 5D-5L), Short Form 36Item (SF-36), and Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F), Ulcerative Colitis Symptoms Questionnaire(UC-SQ), and Patient Global Impression of Severity (PGIS; only in selectsites) during the study at Baseline, Week 2, and Week 8/PD for Part 1.These same questionnaires will be completed at Week 16/PD for Part 2.Subjects will be asked to fill out the Patient Global Impression ofChange (PGIC) during the study at Week 2, and Week 8/PD for Part 1. Thissame questionnaire will be completed at Week 16/PD for Part 2. Duringeach study visit subjects will also be asked to report UC-relatedhospitalizations and surgeries which will be captured as a part of thesupplemental Health Care Resource Utilization (HCRU) form of AdverseEvent collection in electronic data capture.

Subjects will be discontinued from the study if they withdraw consent orif they are deemed unsuitable to continue for any reason by theinvestigator.

Washout Period:

Subjects, who have been taking exclusionary medications prior toscreening must complete medication washout. The duration is based on theexcluded medication as described in the protocol. However, for subjectswho have discontinued infliximab, certolizumab, adalimumab, golimumab,vedolizumab, natalizumab, ustekinumab, if there is proper documentationof an undetectable drug level measured by a commercially available assayfor any of the approved biologics above, there is no minimum washoutprior to Baseline. Protocol-related adverse events should be reviewedand subjects must complete the washout prior to the Baseline Visit.

Concomitant UC-Related Medications (Oral Corticosteroids, Antibiotics,Aminosalicylates, and/or Methotrexate):

Parts 1 and 2

All UC-related concomitant medications should be kept on stable doses inParts 1 and 2. All subjects receiving stable dose of UC-relatedantibiotics (those subjects who did not discontinue), aminosalicylates,or MTX at Week 0 will maintain their concomitant treatments andrespective doses through the end of the study. Dose may be decreased orterminated in the event of moderate to severe treatment related toxicity(e.g., leukopenia or elevated liver enzymes) in the opinion of theinvestigator.

Diagnosis and Main Criteria for Inclusion/Exclusion: Main Inclusion:

1. Male or female between 16 and 75 years of age at Baseline. Adolescentsubjects 16 and 17 years old will only be enrolled if approved by thecountry or regulatory/health authority and must weigh ≥40 kg and meetthe definition of Tanner Stage 5 (refer to Appendix H) at the screeningvisit. If these approvals have not been granted, only subjects ≥18 yearsold will be enrolled.2. Diagnosis of UC for 90 days or greater prior to Baseline, confirmedby colonoscopy during the Screening Period, with exclusion of currentinfection, colonic dysplasia and/or malignancy. Appropriatedocumentation of biopsy results consistent with the diagnosis of UC, inthe assessment of the Investigator, must be available.3. Active UC with an Adapted Mayo score of 5 to 9 points and endoscopicsubscore of 2 to 3 (confirmed by central reader).4. Demonstrated an inadequate response, loss of response, or intoleranceto at least one of the following treatments including, oralaminosalicylates, corticosteroids, immunosuppressants, and/or biologictherapies, in the opinion of the investigator, as defined below:

-   -   Note: An inadequate response, loss of response, or intolerance        to Oral Aminosalicylates will NOT count towards eligibility for        the following countries: Austria, Czechia, Finland, France,        Ireland, Italy, Latvia, Lithuania, Norway, Poland, Portugal,        Spain, Sweden and United Kingdom.    -   Oral aminosalicylates (e.g., mesalamine, sulfasalazine,        olsalazine, balsalazide)        -   Signs and symptoms of persistently active disease, in the            opinion of the investigator, during a current or prior            course of at least 4 weeks of treatment with 2.4 g/day            mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or            6.75 g/day balsalazide.    -   Corticosteroids        -   Signs and symptoms of persistently active disease despite a            history of at least one induction regimen that included a            dose equivalent to prednisone ≥40 mg/day orally for at least            3 weeks or intravenously for 1 week, OR        -   Unable to taper corticosteroids to below a dose equivalent            to prednisone 10 mg daily orally without recurrent active            disease, OR        -   Signs and symptoms of persistently active disease during or            after a course of at least 4 weeks of treatment with 9            mg/day budesonide or 5 mg/day beclomethasone, OR        -   Unable to taper oral budesonide to at or below 6 mg/day            without recurrent active disease, OR        -   History of intolerance to corticosteroids (including, but            not limited to Cushing's syndrome, osteopenia/osteoporosis,            hyperglycemia, insomnia, infection).    -   Immunosuppressants        -   Signs and symptoms of persistently active disease despite a            history of at least one 90 day regimen of oral azathioprine            (≥1.5 mg/kg/day; for subjects in Japan, China, and Taiwan            only: ≥1.0 mg/kg/day), 6-mercaptopurine (6-MP) (≥1            mg/kg/day; [for subjects in Japan, China, and Taiwan only:            ≥0.6 mg/kg/day, rounded to the nearest available tablet of            half tablet formulation] or a documented 6-thioguanine            nucleotide (6-TGN) level of 230-450 pmol/8×10⁸ RBC or higher            on the current dosing regimen), injectable methotrexate            (MTX) (≥15 mg/week subcutaneous [SC] or intramuscular), or            tacrolimus (for subjects in Japan and Taiwan only:            documented trough level of 5-10 ng/mL), OR        -   History of intolerance to at least one immunosuppressant            (including, but not limited to nausea/vomiting, abdominal            pain, pancreatitis, liver enzyme abnormalities, lymphopenia,            infection)        -   Biologic Agents for UC        -   Signs and symptoms of persistently active disease despite a            history of any of the following:        -   at least one 6-week induction regimen of infliximab (≥5            mg/kg IV at 0, 2, and 6 weeks),        -   at least one 4-week induction regimen of adalimumab (one 160            mg SC dose followed by one 80 mg SC dose [or one 80 mg SC            dose in countries where this dosing regimen is allowed]            followed by one 40 mg SC dose at least 2 weeks apart),        -   at least one 2-week induction regimen of golimumab (one 200            mg SC dose followed by one 100 mg SC dose at least 2 weeks            apart),        -   at least one 6-week induction regimen of vedolizumab (300 mg            W at 0, 2, and 6 weeks),        -   at least one induction regimen of ustekinumab, a single W            dose using weight-based dosing (260 mg for subjects with            body ≤55 kg; 390 mg for subjects with body weight >55 kg to            ≤85 kg; 520 mg for subjects with body weight >85 kg OR        -   Recurrence of symptoms during scheduled maintenance dosing            following prior clinical benefit (discontinuation despite            clinical benefit does not qualify), OR        -   History of intolerance to at least one biologic agent            (including, but not limited to infusion-related reaction,            demyelination, congestive heart failure, infection) Note:            Non-bio-IR subjects who have received a prior biologic for            up to 1 year may be enrolled, however, subjects must have            discontinued the biologic for reasons other than inadequate            response or intolerance (e.g., change of insurance, well            controlled disease), and must meet the criteria for            inadequate response, loss of response or intolerance to            aminosalicylates, corticorsteroids and/or immunosuppressants            as defined above.            Note: Oral MTX use is allowed during the study, however            prior or current use of oral MTX is not sufficient for            inclusion into the study unless these subjects were            previously treated with aminosalicylates, corticosteroids or            immunosuppressants (azathioprine or 6-MP) and have            inadequate response to, loss of response to or intolerance            to the therapy as defined above.

Main Exclusion:

1. Subject with current diagnosis of Crohn's disease (CD) or diagnosisof indeterminate colitis (IC).2. Current diagnosis of fulminant colitis and/or toxic megacolon.3. Subject with disease limited to the rectum (ulcerative proctitis)during the Screening endoscopy.4. Received cyclosporine, tacrolimus, mycophenolate mofetil orthalidomide within 30 days prior to Baseline.5. Subject who received azathioprine or 6-MP within 10 days of Baseline.6. Received intravenous corticosteroids within 14 days prior toScreening or during the Screening Period.7. Subject with previous exposure to JAK inhibitor (e.g., tofacitinib,baricitinib, filgotinib, upadacitinib).8. Screening laboratory and other analyses show any of the followingabnormal results:

-   -   Serum Aspartate Transaminase (AST) or Alanine Transaminase        (ALT)>2.0×upper limit of the reference range (ULN);    -   Estimated glomerular filtration rate (eGFR) by simplified        4-variable Modification of Diet in Renal Disease (MDRD) formula        <30 mL/min/1.73 m²;    -   Total White Blood Cell (WBC) count <2500/μL;    -   Absolute neutrophil count (ANC)<1,200/μL;    -   Platelet count <100,000/μL;    -   Absolute lymphocytes count <750/μL;    -   Hemoglobin <9 g/dL.

Investigational Product: Upadacitinib (ABT-494) Doses:

-   -   Part 1: Upadacitinib 45 mg QD (blinded)    -   Part 2: Upadacitinib 45 mg QD (open-label)    -   Mode of Administration: Oral

Reference Therapy: Part 1: Matching Placebo, Oral

DURATION OF TREATMENT: 8 weeks for subjects achieving clinical responseat week 8; or 16 weeks for subjects who do not achieve clinical responseat week 8.

Criteria for Evaluation: Efficacy: Primary Endpoint:

The primary endpoint for Study M14-675 is the proportion of subjects whoachieve clinical remission per Adapted Mayo score (defined as stoolfrequency subscore [SFS]≤1 and not greater than baseline, RBS of 0, andendoscopic subscore ≤1) at Week 8. Note: evidence of friability duringendoscopy in subjects with otherwise “mild” endoscopy activity willconfer an endoscopic subscore of 2.

Ranked Secondary Endpoints:

-   -   1. Proportion of subjects with endoscopic improvement at Week 8    -   2. Proportion of subjects with endoscopic remission at Week 8    -   3. Proportion of subjects achieving clinical response per        Adapted Mayo Score at Week 8    -   4. Proportion of subjects achieving clinical response per        Partial Adapted Mayo score (defined as decrease from Baseline ≥1        points and ≥30% from Baseline, PLUS a decrease in RBS≥1 or an        absolute RBS≤1) at Week 2    -   5. Proportion of subjects achieving histologic-endoscopic        mucosal improvement at Week 8    -   6. Proportion of subjects who reported no bowel urgency at Week        8    -   7. Proportion of subjects who reported no abdominal pain at Week        8    -   8. Proportion of subjects who achieved histologic improvement at        Week 8    -   9. Change from Baseline in IBDQ total score at Week 8    -   10. Proportion of subjects with mucosal healing at Week 8    -   11. Change from Baseline in FACIT-F score at Week 8.

Pharmacokinetic:

Blood samples will be collected for measurement of upadacitinib plasmaconcentration at Week 2, Week 6, and Week 8/PD in Part 1.

Safety:

Safety analyses will be performed on all subjects who receive at leastone dose of study drug. Incidence of AEs, changes in vital signs,electrocardiogram, physical examination results, and clinical laboratorydata will be assessed.

Exploratory Research Variables and Validation Studies (Optional):

Prognostic, predictive and pharmacodynamics biomarkers signatures may beinvestigated. Samples for different applications, includingpharmacogenetic, epigenetic, transcriptomic, proteomic and targetedinvestigations will be collected at various time points. Assessmentswill include but may not be limited to nucleic acids, proteins,metabolites or lipids.

8-Week Induction Period—Part 1

This period will begin at the Baseline Visit (Week 0) and will end atthe Week 8 Visit. At the Baseline Visit, subjects who meet all theinclusion criteria and none of the exclusion criteria described hereinwill be enrolled into the study and randomized to the double-blindinduction period. During this period of the study, subjects will visitthe study site at Weeks 2, 4, 6, and 8. A ±3-day window is permittedaround scheduled study visits. The last dose of study drug during thisperiod is recommended to be taken the day prior to the Week 8 Visit whenpossible.

8-Week Extended Treatment Period—Part 2

The period will begin after the Week 8 endoscopy in Part 1 and will endat the Week 16 Visit.

At Week 8, subjects in Part 1 who did not achieve clinical response(defined by Adapted Mayo Score) will be enrolled into Part 2 and receiveopen label upadacitinib 45 mg QD for an additional 8 weeks. Clinicalresponse is defined as decrease from baseline in the Adapted Mayo score≥2 points and ≥30% from baseline, PLUS a decrease in rectal bleedingscore (RBS)≥1 or an absolute RBS≤1.

If the subject is a clinical responder at Week 8/16, the subject mayenter Study M14-533 Cohort 1. If the subject is a clinical non-responderat Week 8, the subject may enter Part 2. If the subject is a clinicalnon-responder at Week 16 the subject will discontinue from the study.During this period of the study, subjects will visit the study site atWeeks 10, 12, 14, and 16. A ±3-day window is permitted around scheduledstudy visits. The last dose of study drug during this period isrecommended to be taken the day prior to the Week 16 Visit whenpossible.

Re-Screen

Subjects that initially screen fail for the study will be permitted tore-screen following re-consent. For any subjects who screened and whowere unable to enter the program during Study M14-234 Substudy 1 due toenrollment limits, these subjects may also be rescreened into StudyM14-234 Substudy 2 or Study M14-675.

The subject must meet all the inclusion and none of the exclusioncriteria at the time of re-screening in order to qualify for the study.There is no minimum period of time a subject must wait to re-screen forthe study and there is no maximum number of re-screens allowed for agiven subject. If the subject had a complete initial screeningevaluation including the assessment of a purified protein derivative(PPD) test (or equivalent), or Interferon-Gamma Release Assay (IGRA;QuantiFERON-TB Gold Plus test or T-SPOT TB test), chest x-ray, hepatitisB virus (HBV), hepatitis C virus (HCV), HIV, Beta-D-glucan (Japan only)and electrocardiogram (ECG), these tests will not be required to berepeated for re-screening provided the conditions noted herein are metand no more than 90 calendar days have passed since the date of testing.

If a subject is being rescreened within 14 days (from the date of theprevious screening testing), it is not required to repeat Screeningtesting for chemistry/hematology, urinalysis, serum pregnancy, andClostridium difficile (C. difficile).

An endoscopy with biopsy will not be required to be repeated forre-screening provided the conditions noted herein are met and re-consentis no more than 30 calendar days after the initial screening endoscopy.

All other screening procedures will be repeated. As appropriate, sitesare encouraged to contact the AbbVie TA MD to confirm if subjects shouldor should not be re-screened. Re-screened subjects will retain the samesubject number assigned at the initial screening.

Efficacy Variables

The following endpoint definitions apply to the efficacy variablesdescribed below:

Clinical Remission:

Per Adapted Mayo: SFS≤1 and not greater than baseline, RBS of 0, andendoscopic subscore ≤1 (note: evidence of friability during endoscopy insubjects with otherwise “mild” endoscopic activity will confer anendoscopic subscore of 2).

Per Full Mayo: Full Mayo score of ≤2 with no subscore >1

Clinical Response:

-   -   Per Adapted Mayo: decrease from baseline in Adapted Mayo score        ≥2 points and ≥30%, accompanied by a decrease in RBS of ≥1 or an        absolute RBS of 0 or 1    -   Per Full Mayo: decrease from baseline in Full Mayo score ≥3        points and ≥30%, accompanied by a decrease in RBS of ≥1 or an        absolute RBS of 0 or 1    -   Per Partial Adapted Mayo: decrease from Baseline ≥1 points and        ≥30% from Baseline, PLUS a decrease in RBS≥1 or an absolute        RBS≤1    -   Endoscopic remission: Endoscopic subscore of 0    -   Endoscopic improvement: Endoscopic subscore ≤1    -   Histologic improvement: Decrease from Baseline in Geboes score    -   Histologic-endoscopic mucosal improvement: Endoscopic subscore        ≤1 and Geboes score ≤3.1    -   Mucosal healing: Endoscopic subscore=0 and Geboes score <2

Primary Variable

The primary endpoint is the proportion of subjects who achieve clinicalremission per Adapted Mayo score (defined as SFS≤1 and not greater thanbaseline, RBS of 0, and endoscopic subscore ≤1) at Week 8. Note:Evidence of friability during endoscopy in subjects with otherwise“mild” endoscopic activity will confer an endoscopic subscore of 2.

Secondary Variables

-   -   Ranked secondary efficacy variables are as follows:    -   Proportion of subjects with endoscopic improvement at Week 8    -   Proportion of subjects with endoscopic remission at Week 8    -   Proportion of subjects achieving clinical response per Adapted        Mayo Score at Week 8    -   Proportion of subjects achieving clinical response per Partial        Adapted Mayo score (defined as decrease from Baseline ≥1 points        and ≥30% from Baseline, PLUS a decrease in RBS≥1 or an absolute        RBS≤1) at Week 2    -   Proportion of subjects achieving histologic-endoscopic mucosal        improvement at Week 8    -   Proportion of subjects who reported no bowel urgency at Week 8    -   Proportion of subjects who reported no abdominal pain at Week 8    -   Proportion of subjects who achieved histologic improvement at        Week 8    -   Change from Baseline in IBDQ total score at Week 8    -   Proportion of subjects with mucosal healing at Week 8    -   Change from Baseline in FACIT-F score at Week 8

Additional Variables

-   -   Additional efficacy variables are as follows and will be        evaluated.    -   Proportion of subjects achieving response in IBDQ Bowel Symptom        domain (increase of IBDQ bowel symptom domain score ≥6) at Week        8    -   Proportion of subjects with UC-related hospitalizations through        Week 8    -   Proportion of subjects with UC-related surgeries through Week 8    -   Proportion of subjects achieving response in IBDQ fatigue item        (increase of IBDQ fatigue item score ≥1) at Week 8    -   Proportion of subjects with SFS of 0, RBS of 0 and endoscopic        subscore of 0 at Week 8    -   Proportion of subjects with SFS of 0, RBS of 0 and endoscopic        subscore of ≤1 at Week 8    -   Proportion of subjects achieving clinical remission per Full        Mayo Score (defined as a full Mayo score ≤2 with no        sub-score >1) at Week 8    -   Change in Full Mayo Score from Baseline to Week 8    -   Proportion of subjects achieving clinical remission per Partial        Mayo score over time.    -   Proportion of subject achieving clinical response per Partial        Adapted Mayo score over time    -   Proportion of subjects achieving clinical response per Partial        Mayo score over time.    -   Proportion of subjects with SFS≤1 over time.    -   Proportion of subjects with RBS=0 over time.    -   Proportion of subjects with SFS≤1 at Week 2.    -   Proportion of subjects with RBS of 0 at Week 2.    -   Proportion of subjects with fecal calprotectin below 150 mg/kg        over time.    -   Change from Baseline in fecal calprotectin over time    -   Change from Baseline in hs-CRP over time.    -   Change from Baseline in Partial Adapted Mayo score, Partial Mayo        score and SFS, RBS over time.    -   Change from Baseline in UCEIS score over time.    -   Change from Baseline in laboratory and nutritional parameters        (e.g., hemoglobin, hematocrit, albumin, total protein        concentration, and weight).

Change from Baseline in subject-reported stool frequency (absolutevalues).

-   -   Change from Baseline in IBDQ total and domain score over time.    -   Change from Baseline in individual IBDQ item under Bowel Symptom        domain (for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29)        over time.    -   Proportion of subjects with IBDQ response (increase of IBDQ≥16        from Baseline) over time.    -   Proportion of subjects with IBDQ remission (IBDQ total score        ≥170) over time.    -   Change from Baseline in European Quality of Life—5 Dimensions 5        Levels (EQ-5D-5L) score over time.    -   Change from Baseline in WPAI scores over time.    -   Change from Baseline in SF-36 Physical Component Summary (PCS)        and Mental Component Summary (MCS) components and domain scores        over time.    -   Proportion of subjects by Patient Global Impression of Change        (PGIC) category over time.    -   Proportion of subjects by Patient Global Impression of Severity        (PGIS) category over time.    -   Change from Baseline in Functional Assessment of Chronic Illness        Therapy-Fatigue (FACIT-F) score over time.    -   Change from Baseline in Ulcerative Colitis Symptoms        Questionnaire (UC-SQ) score over time    -   Proportion of subjects with all cause hospitalization through        Week 8    -   Proportion of subjects with all cause surgery through Week 8

Results

Results of this study are provided in FIGS. 24 to 28C. Generally,upadacitinib 45 mg QD met primary and all ranked secondary endpoints(all achieved p<0.001), demonstrating superiority vs placebo as aninduction therapy. This efficacy was demonstrated across clinical,endoscopic and histologic endpoints. At week 8, approximately 75% ofpatients showed a clinical response (FIGS. 25 and 26B). Of the remaining25% of non-responding patients, approximately 50% showed a clinicalresponse by 16 weeks. Particularly surprising was the extent of mucosalhealing observed after 8 weeks of induction, as defined by an endocopicscore of 0 and a Geboes score of less than 2. The proportion of subjectsachieving the primary endpoint of clinical remission per Adapted Mayoscore at Week 8 was significantly higher in the upadacitinib 45 mg QDgroup (33.5%) compared to the placebo group (4.1%) with p-value <0.001.Clinical response per Partial Adapted Mayo Score was seen as early asWeek 2

Overall, the eight-week treatment with upadicitinib 45 mg QD as aninduction therapy was well tolerated. No new safety risks were observedcompared to the known safety profile of upadacitinib. The rates ofsevere adverse events (AE) and AEs leading to study drug discontinuationwere lower with upadacitinib 45 mg as compared to placebo. No deathswere reported in the study. The rates of neutropenia, lymphopenia,hepatic disorder, and CPK elevation were higher with upadacitinib 45 mgQD as compared to placebo. The rate of anemia AEs was higher withupadacitinib 45 QD; however, Grade 3 hemoglobin decrease occurred morefrequently on placebo. No reports of active TB, malignancy, adjudicatedGI perforation, adjudicated VTE, or adjudicated MACE were made in theupadacitinib 45 mg QD group. One event each of adjudicated GIperforation and VTE (PE and DVT) was reported in the placebo group.

Example 20: Upadacitinib 15 mg or 30 mg as Maintenance Therapy forUlcerative Colitis

Approximately 750 subjects who achieved clinical response per AdaptedMayo Score after completion of induction treatment or Extended TreatmentPeriod in Study M14-234 Substudy 1, Substudy 2, or Study M14-675, wereeligible to enter this trial (Substudy 3) and treated with a blindedtreatment assignment for up to 52 weeks. Subjects with missing Week 8or/and Week 16 endoscopy during the period of COVID-19 pandemic were noteligible to enter Substudy 3. Subjects from Study M14-675 were requiredto have achieved clinical response at Week 8 or 16. The Baseline Visitof Substudy 3 was completed on the same day as the final visit in theInduction Phase (either at Week 8 or Week 16) for subjects who wereeligible.

Clinical response was defined as a decrease from baseline in the AdaptedMayo score ≥2 points and ≥30% from baseline, PLUS a decrease in RBS≥1 oran absolute RBS≤1. The treatment assignment in Substudy 3 depended onthe treatment received in Substudies 1 and 2, or Study M14-675, asdetailed below. Substudy 3 included 4 cohorts:

Cohort 1:

The approximately 525 subjects who achieved clinical response in StudyM14-234 Substudies 1 and 2, or Study M14-675, and received 1 of thefollowing treatments, were re-randomized in a 1:1:1 ratio to one of thetreatment groups in Cohort 1:

-   -   Upadacitinib 30 mg QD or 45 mg QD in Study M14-234 Substudy 1    -   Upadacitinib 45 mg QD in Study M14-234 Substudy 2 Part 1    -   Upadacitinib 45 mg QD in Study M14-675 Part 1    -   Placebo QD in Study M14-234 Substudy 2 Part 1 followed by        upadacitinib 45 mg QD in Study M14-234 Substudy 2 Part 2    -   Placebo QD in Study M14-675 Part 1 followed by upadacitinib 45        mg QD in Part 2    -   Treatment groups in Cohort 1:        -   Group 1: upadacitinib 15 mg QD        -   Group 2: upadacitinib 30 mg QD        -   Group 3: placebo QD

Subjects who achieved clinical response and received upadacitinib 15 mgQD in Study M14-234 Substudy 1 were re-randomized 1:1 to only receiveupadacitinib 15 mg QD or placebo QD (treatment Group 1 or 3).

Cohort 2:

Approximately 60 subjects who received double-blind placebo QD treatmentfor 8 weeks during Study M14-234 Substudy 1, Substudy 2 Part 1 or StudyM14-675 Part 1 and achieved clinical response continued to receiveblinded placebo QD in Substudy 3.

Cohort 3:

Approximately 150 subjects who received upadacitinib 45 mg QD ininduction phase and did not achieve clinical response—and receivedupadacitinib 45 mg in Extended Treatment in Study M14-234 (Substudy 2,Part 2) or Study M14-675 (Part 2) and achieved clinical response at Week16 were re-randomized 1:1 and received blinded upadacitinib 30 mg QD orupadacitinib 15 mg QD in Study M14-234 (Substudy 3).

Cohort 4:

Approximately 15 subjects who received double-blinded treatment ofupadacitinib 7.5 mg for 8 weeks during Study M14-234 (Substudy 1) andachieved clinical response continued to receive blinded treatment ofupadacitinib 7.5 mg QD in Substudy 3. The schematic of Substudy 3 isprovided in Table 30.

TABLE 30 Substudy 3 schematic. M14-234 Substudy 3 (Maintenance study;Cohorts Status week 0-52) Cohort 1: Re-randomized Double blind (DB)Clinical responders to upadacitinib upadacitinib from: 15 mg QD; M14-234SS1* (not including n = 150 7.5 mg QD) DB upadacitinib SS2 or M14-675(week 8) 30 mg QD; Extended treatment clinical n = 150 responders (week16) who DB placebo QD; received placebo in induction n = 150 Cohort 2:Do not get DB placebo QD Placebo clinical responders re-randomized (week8) from M14-234 SS1, SS2, or M14-675 Cohort 3: Re-randomized DBupadacitinib Clinical responders (week 16) to 15 mg QD upadacitinib fromthe extended DB upadacitinib treatment period in M14-234 30 mg QD SS2and M14-675 who received upadacitinib in induction Cohort 4: Do not getDB upadacitinib Clinical responders (week 8) to re-randomized 7.5 mg QDupadacitinib 7.5 mg QD in M14- 234 SS1 *Responders who receivedupadacitinib 15 mg QD in M14-234 SS1 will only be randomized to receiveupadacitinib 15 mg QD or placebo QD

The rationale for re-randomizing only induction responders who receivedupadacitinib 15, 30 or 45 mg QD from Substudy 1 is to ensure that nosubject receives a dose during maintenance that is higher than what wasreceived in the induction period.

During Substudy 3, subjects who met the criteria for initial loss ofresponse after at least 2 weeks of treatment and had a second confirmedloss of response on a consecutive visit at least 14 days later had theoption to enroll into Study M14-533 and receive open-label upadacitinib.

Loss of response is defined as follows: A subject who presents with anSFS and RBS score each at least 1 point greater than theend-of-induction value (Week 8 of Substudy 1, Substudy 2 Part 1, StudyM14-675 Part 1 or Week 16 of Substudy 2 Part 2 or Study M14-675 Part 2)on two consecutive visits at least 14 days apart, associated with thepresence of signs or symptoms of progression of UC.

For subjects with SFS or RBS≥2.1 at the end-of-induction, loss ofresponse is defined as: An increase in either the SFS or RBS of at least1 point greater than the end-of-induction value on two consecutivevisits at least 14 days apart and associated with the presence of signsor symptoms of progression of UC disease.

Subjects who entered Substudy 3 from Study M14-234 Substudy 1 were onlyrequired to complete 44 weeks of maintenance therapy in Substudy 3.Subjects entering Substudy 3 from Study M14-234 Substudy 2 or from StudyM14-675 were required to complete 52 weeks in Substudy 3 if they did notwithdraw or have loss of response prior.

Screening

Subjects, who have been taking exclusionary medications prior toscreening or Baseline were required to complete medication washout. Theduration was based on the excluded medication. During Screening,biologic drug levels could be optionally assessed as an alternative tocompleting the required washout period as follows: (1) infliximab andnatalizumab: may be tested approximately 4 weeks or later from the lastdose; (2) adalimumab, certolizumab, golimumab, or vedolizumab: may betested approximately 6 weeks or later from the last dose; (3)ustekinumab: may be tested approximately 8 weeks or later from the lastdose. If the biologic drug was not detected, the subject was consideredas eligible and the washout period was not required.

Concomitant UC-Related Medications (Oral Corticosteroids, Antibiotics,Aminosalicylates, and/or Methotrexate):

At Baseline of Substudy 3 (Week 8 or Week 16 of Study M14-234 Substudy1, Substudy 2, and Study M14-675), subjects who were takingcorticosteroid therapy will have their corticosteroid therapy tapered.Subjects taking corticosteroids who have worsening of disease after thesteroid taper has been initiated may have had their corticosteroid doseincreased. Use of inhaled or topical dermatologic corticosteroids wasnot restricted.

All subjects receiving UC-related antibiotics may discontinue treatmentstarting at Week 0 of Substudy 3 at the discretion of the investigator.

All subjects receiving stable dose of UC-related antibiotics (thosesubjects who did not discontinue), aminosalicylates, or MTX at Week 0maintained their concomitant treatments and respective doses through theend of the study. Dose was allowed to be decreased or terminated in theevent of moderate to severe treatment related toxicity (e.g., leukopeniaor elevated liver enzymes. If the subject and investigator chose toreceive/administer live vaccines, these vaccinations were completed (perlocal label) at least 30 days (8 weeks for subjects in Japan) beforefirst dose of study drug. Live vaccinations were prohibited during studyparticipation including at least 30 days (or longer if required locally)after the last dose of study drug.

Efficacy Assessment

The primary endpoint for Phase 3 maintenance (Substudy 3) is theproportion of subjects who achieve clinical remission per Adapted Mayoscore at Week 52 (for subjects who enrolled under the protocol with44-week maintenance period, these will apply at Week 44, as applicable).

Ranked secondary efficacy variables for Phase 3 Maintenance (Substudy 3)are as follows:

-   -   At Week 52 (for subjects who enrolled under the protocol with        44-week maintenance period, these will apply at Week 44, as        applicable):        -   1. Proportion of subjects with endoscopic improvement        -   2. Proportion of subjects who maintain clinical remission            per Adapted Mayo score among subjects who achieved clinical            remission per Adapted Mayo score in Study M14-234 (Substudy            1 or 2) or Study M14-675        -   3. Propotion of subjects who achieved clinical remission at            Week 52 per adapted Mayo score and were corticosteroid free            for ≥90 days among subjects in clinical remission in the end            of the induction treatment in Study M14-234 (Substudy 1            or 2) or Study M14-675.        -   4. Proportion of subjects with endoscopic improvement among            subjects with endoscopic improvement in Study M14-234            (Substudy 1 or 2) or Study M14-675        -   5. Proportion of subjects with endoscopic remission        -   6. Proportion of subjects maintain clinical response per            Adapted Mayo score        -   7. Proportion of subjects with histologic-endoscopic mucosal            improvement        -   8. Change from Baseline in IBDQ total score        -   9. Proportion of subjects with mucosal healing        -   10. Proportion of subjects who reported no bowel urgency        -   11. Proportion of subjects who reported no abdominal pain        -   12. Change from Baseline in FACIT-F score

Definitions of Mayo, Partial Mayo, and Adapted Mayo scores are providedin Table 31.

TABLE 31 Mayo, Partial Mayo, and Adapted Mayo Score Definitions RectalStool Physician's Global Bleeding Frequency Assessment [PGA] EndoscopyScore [RBS] (0-3) [SFS] (0-3) (0-3) (0-3) Range Mayo Score X X X X  0-12Partial Mayo Score X X X 0-9 Adapted Mayo Score X X X 0-9 PartialAdapted X X 0-6 Mayo Score

Additional efficacy variables are as follows and will be evaluated:

-   -   Proportion of subjects who discontinued corticosteroid use,        remained corticosteroid free for ≥90 days immediately before        Week 52 and achieved clinical remission per Adapted Mayo score        in subjects taking steroids at Baseline (of induction)    -   Proportion of subjects achieving response in IBDQ Bowel Symptom        domain at Week 52 (increase of IBDQ bowel symptom domain score        ≥6)    -   Proportion of subjects achieving response in IBDQ fatigue item        at Week 52 (increase of IBDQ fatigue item score ≥1)    -   Proportion of subjects who are taking corticosteroids at        Baseline (of induction) and are steroid-free over time.    -   Proportion of subjects who are taking corticosteroid at Baseline        (of induction) and are steroid free at Week 52    -   subjects who discontinued corticosteroid use and achieved        clinical remission per Adapted Mayo score at Week 52 in subjects        taking steroids at Baseline (of induction)    -   Proportion of subjects achieving clinical remission per Full        Mayo Score (defined as a full Mayo score ≤2 with no        sub-score >1) at Week 52    -   Proportion of subjects who discontinued corticosteroid use and        achieved clinical remission per Partial Mayo Score over time in        subjects taking steroids at baseline (of induction)    -   Proportion of subjects who discontinued corticosteroid use of        ≥90 days immediately before Week 52 and achieved clinical        remission at Weeks 0 and Week 52 of Substudy 3, in subjects who        were taking steroids at Baseline (of induction)    -   Proportion of subjects who discontinued corticosteroid use of        ≥90 days immediately before Week 52 and achieved a SFS≤1 (and        not worse than Baseline of induction) and RBS=1 at Weeks 36 and        44 and clinical remission at Week 52, in subjects who were        taking steroids at baseline (of induction)    -   Proportion of subjects achieving clinical remission per Partial        Mayo score over time.    -   Proportion of subjects with SFS of 0, RBS of 0 and endoscopic        subscore of 0 at Week 52    -   Proportion of subjects with SFS of 0, RBS of 0 and endoscopic        subscore of ≤1 at Week 52    -   Proportion of subjects with SFS≤1, RBS=0 at Week 28 and clinical        remission per adapted Mayo score at Week 52    -   Proportion of subjects with SFS≤1, RBS=0 at Week 28 and Week 52    -   Proportion of subjects with SFS of 0, RBS of 0, and endoscopic        subscore of 0 over time.    -   Proportion of subjects achieving clinical response per Partial        Mayo score over time.    -   Proportion of subjects with SFS≤1 over time.    -   Proportion of subjects with RBS of 0 over time.    -   Proportion of subjects with fecal calprotectin below 150 mg/kg        over time.    -   Change from Baseline in hs-CRP over time.    -   Change from Baseline in fecal calprotectin over time Change from        Baseline in corticosteroid dose over time.    -   Change from Baseline in Adapted Mayo score, Partial Adapted Mayo        score, Full Mayo score, Partial Mayo score and Mayo subscores        over time.    -   Change from Baseline in UCEIS score over time.    -   Proportion of subjects with histologic improvement at Week 52    -   Proportion of subjects with histologic remission at Week 52    -   Proportion of subjects with histologic remission (defined as        Geboes score <2) at Weeks 8, or Week 16, and Week 52.    -   Change from Baseline in histologic score over time.    -   Change from Baseline in laboratory and nutritional parameters        (e.g., hemoglobin, hematocrit, albumin, total protein        concentration, and weight).    -   Change from Baseline in subject-reported stool frequency        (absolute values).    -   Change from Baseline in IBDQ total and domain score over time.    -   Change from Baseline in individual IBDQ item under Bowel Symptom        domain (for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29)        overtime.    -   Proportion of subjects with IBDQ response (increase of IBDQ≥16        from Baseline) over time.    -   Proportion of subjects with IBDQ remission (IBDQ total score        ≥170) over time.    -   Change from Baseline in EQ-5D-5L score over time.    -   Change from Baseline in WPAI scores over time.    -   Change from Baseline in SF-36 PCS, MCS components and domain        scores over time.    -   Proportion of subjects by PGIC category over time.    -   Proportion of subjects by PGIS category over time.    -   Change from Baseline in UC-SQ score over time.    -   Health care resource utilization (all-cause and UC-related        hospitalizations and surgeries) during the study.    -   Incidence rate of UC-related hospitalizations.    -   Incidence rate of UC-related surgeries.    -   In addition, change from Week 0 of Substudy 3 will be summarized        for hs-CRP, fecal calprotectin, IBDQ total and domain score,        EQ-5D-5L score, FACIT-F score, and other PRO endpoints, as        applicable.

The following outcomes and questionnaires will be completed:

-   -   IBDQ—Inflammatory Bowel Disease Questionnaire. The IBDQ is a        disease-specific instrument composed of 32 Likert-scaled items.        The total score ranges from 32 to 224 using the 7-point response        options, with higher scores indicating better health-related        quality of life. The IBDQ scale contains 4 component subscales:        bowel symptoms, systemic symptoms, emotional function, and        social function. Each subscale can be computed with total scores        ranging from 10 to 70, 5 to 35, 12 to 84, and 5 to 35,        respectively. In some embodiment, patients treated according to        the disclosed method exhibit a change (increase from baseline)        in the IBDQ score.    -   SF-36—Short Form 36. The SF-36 questionnaire is a        self-administered multi-domain scale with 36 items. Eight        subscales cover a range of functioning: physical functioning,        role-physical, bodily pain, general health, vitality, social        functioning, role-emotional, and mental health. The scoring        yields a physical component score, a mental component summary        score, and subscale scores. Higher scores represent better        outcomes. The concepts measured by the SF-36 are not specific to        any age, disease, or treatment group, allowing comparison of        relative burden of different diseases and the benefit of        different treatments.    -   EQ-5D-5L—European Quality of Life 5 Dimensions 5 Levels. The        EQ-5D-5L is a standardized non-disease specific instrument for        describing and valuing health-related quality of life. The        EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual        activity, pain/discomfort, and anxiety/depression. Each        dimension has 5 levels: no problem, slight problem, moderate        problem, severe problem or unable to do the activity. It also        contains a Visual Analogue Scale (VAS). Subjects are asked to        indicate the level that describes their current level of        function or experience for each dimension. As a measure of        health status, it provides a descriptive profile and can be used        to generate a single index value for health status, where full        health is equal to 1 and death is equal to 0. The VAS records        the subject's assessment of his/her own health along a vertical        20 cm line, which has health state scores between 0 and 100.    -   FACIT-F—Functional Assessment of Chronic Illness        Therapy-Fatigue. The FACIT system is a collection of quality of        life (QOL) questionnaires targeted to the management of cancer        and other chronic illnesses. The FACIT fatigue (FACIT-F)        questionnaire was developed to assess fatigue associated with        anemia. It consists of 13 fatigue-related questions. The        responses to the 13 items on the FACIT fatigue questionnaire are        each measured on a 4-point Likert scale. The responses to the        answers are the following: (i) not at all: 0 points; (ii) a        little bit: 1 point; (iii) somewhat: 2 points; (iv) quite a bit:        3 points; (v) very much: 4 points. Thus, the total score ranges        from 0 to 52. High scores represent less fatigue. In some        embodiment, patients treated according to the disclosed method        exhibit a change (reduction from baseline) in the FACIT-F score.    -   WPAI—Work Productivity and Activity Impairment Questionnaire        Ulcerative Colitis. The Work Productivity and Activity Index        assesses the impact of the condition on work productivity losses        and impairment in daily activity. WPAI has six items covering        four domains: (1) Absenteeism (work time missed), measured as        the number of hours missed from work in the past 7 days due to a        condition related problems. Scores are expressed as impairment        percentages, adjusting for hours actually worked according to        the WPAI scoring algorithm; (2) Presenteeism (impairment at        work/reduced on-the-job effectiveness), measured as the impact        of the condition on productivity while at work (i.e., reduced        amount or kind of work, or not as focused as usual). Responses        are recorded on a 0-10 Likert scale (where, 0=no effect of UC on        work and 10=severe impact of UC while at work); (3) Productivity        loss (overall work impairment), measured as the sum of hours        missed due to condition (i.e., absenteeism) and number of hours        worked with impairment (i.e., product of number of hours worked        and presenteeism); and (4) Activity impairment (i.e., activities        other than paid work like work around house, cleaning, shopping,        traveling, studying), recorded and scored in the same way as        presenteeism. Higher numbers indicate greater impairment and        less productivity.    -   PGIC—Patient Global Impression of Change. The PGIC is a        self-administered instrument that assesses change in the overall        symptoms due to UC. The PGIC is one item in which subjects are        asked to rate overall improvement since start of the treatment.        Subjects rate their change as “Very much improved,” “Much        improved,” “Minimally improved,” “No change,” “Minimally worse,”        “Much worse” and Very much worse.    -   PGIS—Patient Global Impression of Severity. The PGIS is a        self-administered instrument that assesses the severity of the        overall symptoms due to ulcerative colitis. The PGIS is one item        in which subjects are asked to rate overall severity of symptoms        over the past week. Subjects rate their change as “Absent,”        “Minimal,” “Mild,” “Moderate,” “Moderately severe,” “Severe” and        “Very severe.”    -   UC-SQ—Ulcerative Colitis Symptoms Questionnaire. The Ulcerative        Colitis Symptoms Questionnaire (UC-SQ) is a UC-specific        instrument composed of 17 items. UC-SQ was developed to assess        UC related gastrointestinal symptoms (e.g., frequent bowel        movements, abdominal pain, cramping) and nongastrointestinal        symptoms (e.g., joint pain and sleep difficulties). Each symptom        item 1-9 can be responded on Likert-type of options such as (i)        Not at all: 0 points; (ii) A little bit: 1 point; (iii)        Somewhat: 2 points; (iv) Quite a bit: 3 points; (v) Very much: 4        points. Each symptom item 10-17 can be responded on Likert-type        of options such as (i) Never: 0 points; (ii) Rarely: 1        point; (iii) Sometimes: 2 points; (iv) Often: 3 points; (v)        Always: 4 points. Overall symptom scores are calculated by        combining ratings of the individual items, with higher scores        indicating greater severity.    -   HCRU—Health Care Resource Utilization. Health Care Resource        Utilization data on number of all-cause and UC-related        hospitalizations and surgeries will be collected

Results

Results of this study are provided in FIGS. 29 to 41E. Overall, thestudy met the primary and all ranked secondary endpoints, demonstratingsuperiority of upadacitinib at doses of 15 mg and 30 mg once daily, asmaintenance therapy for 52 weeks versus placebo (PBO, withdrawal fromupadacitinib treatment; p<0.001) in subjects with moderately to severelyactive Ulcerative Colitis (UC) who responded to 8 weeks of upadacitinib45 mg once daily induction treatment (FIG. 29). The primary endpoint ofclinical remission per Adapted Mayo score at Week 52 was achieved bystatistically significantly higher proportion of subjects in bothupadacitinib treatment groups (42.3% for upadacitinib 15 mg, and 51.7%for upadacitinib 30 mg) than in the PBO group (withdrawal fromupadacitinib treatment: 12.1%; p<0.001). Corticosteroid-free remissionwas achieved in 57% of patients in the 15 mg cohort and 68% of patientsin the 30 mg cohort, and who were in remission at the completion of the8-week induction studies. These rates were significantly higher for the15 mg and 30 mg upadacitinib treated patients relative to the placebogroup (22%; (p<0.001). The maintenance efficacy results are summarizedin Table 32. An overview of primary and ranked secondary endpoints isprovided in FIG. 29.

TABLE 32 Maintenance efficacy result summary Phase 3 MaintenanceEfficacy Results at Week 52*^(,1) Upadacitinib Upadacitinib 15 mg, 30mg, once daily once daily Placebo (n = 148) (n = 154) (n = 149) Clinicalremission^(a) 42% 52% 12% Endoscopic 49% 62% 14% improvement^(b)Histologic-endoscopic 35% 49% 12% mucosal improvement^(c)Corticosteroid-free 57% 68% 22% clinical remission^(d) *Primary endpointwas clinical remission (per Adapted Mayo Score) at week 52. Not allsecondary endpoints are shown. All primary and secondary endpointsachieved p-values of <0.001 versus the placebo group. ^(a)Clinicalremission (per Adapted Mayo Score) is defined as stool frequencysubscore (SFS) ≤1 and not greater than baseline, rectal bleedingsubscore (RBS) of 0 and endoscopic subscore ≤1. ^(b)Endoscopicimprovement is defined as endoscopic subscore ≤1.^(c)Histologic-endoscopic mucosal improvement is defined as anendoscopic subscore of ≤1 and Geboes score ≤3.1. ^(d)Corticosteroid-freeremission is defined as clinical remission at week 52 and corticosteroidfree for ≥90 days prior to week 52 among patients with clinicalremission after 8 weeks of induction treatment. N = 47, 58 and 54 forupadacitinib 15 mg, upadacitinib 30 mg, and placebo group, respectively.

As shown in FIG. 30 and FIG. 31, the clinical response per PartialAdapted Mayo Score and clinical remission rate per Partial Mayo Scorewas maintained over time until Week 52 in both upadacitinib groups.Clear dose response was observed in the primary and most of thesecondary endpoints. The remission rates at 30 mg were generally higherthan at 15 mg across the primary and secondary endpoints, Endoscopicremission and mucosal healing remission rate were similar in the 15 mgand 30 mg groups.

Upadacitinib pharmacokinetics were consistent between the induction andmaintenance periods in subjects with UC. Both upadacitinib doses weregenerally safe and well tolerated in subjects with UC. No new safetyrisks were identified in this UC study compared to the known safetyprofile of upadacitinib.

Statistical Analysis

The primary efficacy objective was assessed on the ITTA population,which was planned to comprise of the first 450 subjects enrolled under52-week maintenance protocol in Cohort 1; subjects received 8-week UPA45 mg QD induction treatment and at least 1 dose of study drug in theMaintenance Study. The 450 subjects were planned to be randomized in a1:1:1 ratio to upadacitinib 15 mg QD, upadacitinib 30 mg QD or placebo.The randomization was stratified by Bio-IR status (Bio-IR; non-Bio-IR)at the Induction Baseline (referred to as Baseline hereafter), clinicalremission status at Week 0 of the Maintenance Study (referred to as Week0 hereafter) (yes; no), corticosteroid usage at Week 0 (yes; no), andinduction dosage for subjects enrolled from the Phase 2b InductionStudy.

The ITTA population included 451 subjects. Key demographics and baselinecharacteristics were generally balanced across treatment groups. Ahigher rate of discontinuation from study drug was observed in placebogroup (65.8%) vs. upadacitinib treatment groups (upadacitinib 15 mg QDgroup 33.1%, and upadacitinib 30 mg 21.4%), primarily due to lack ofefficacy (Table 33).

TABLE 33 Subject disposition Placebo UPA 15 mg QD UPA 30 mg QD Subject(N = 149) (N = 148) (N = 154) Disposition² n (%) n (%) n (%) Completedthe Study Drug 51 (34.2) 99 (66.9) 121 (78.6) Prematurely Discontinued98 (65.8) 49 (33.1) 33 (21.4) from Study Drug Adverse events 14 (9.4) 4(2.7) 8 (5.2) Withdrew consent 1 (0.7) 1 (0.7) 4 (2.6) Lack of efficacy³74 (49.7) 35 (23.6) 12 (7.8) Lost to follow-up 0 0 1 (0.6) COVID-19infection 0 0 1 (0.6) COVID-19 logistical 0 0 1 (0.6) restrictions Other9 (6.0) 9 (6.1) 6 (3.9) ¹ITTA: the first 451 subjects enrolled under52-week maintenance protocol in Cohort 1; subjects received 8-week UPA45 mg QD induction treatment and at least 1 dose of study drug in theMaintenance Study. ²Primary reason. ³Include subjects who early escapedto extension study due to experiencing loss of response (in twoconsecutive visits at least 14 days apart) as defined in the protocol.

Response rate in clinical remission per Adapted Mayo Score at Week 52was consistent across subgroups of Bio-IR and Non-Bio-IR (Table 34 andForest plots (FIG. 32 and FIG. 33)). The 95% confidence intervals forthe treatment difference between each UPA dose and placebo in allsubgroups excluded zero favoring upadacitinib, except those with samplesize <5.

TABLE 34 CLINICAL REMISSION PER ADAPTED MAYO SCORE AT WEEK 52 BY BIO-IRSTATUS (BIO-IR, NON-BIO-IR) (ITTA¹; NRI-C²) Placebo UPA 15 mg UPA 30 mgTreatment Difference vs. PBO (%) Bio-IR N QD N QD N 95% CI³ Status % (n)% (n) % (n) UPA 15 mg UPA 30 mg Bio-IR N = 81 N = 71 N = 73 33.0 41.67.5% (6) 40.5% (29) 49.1% (36) [20.1, 45.9] [28.6, 54.7] Non-Bio-IR N =68 N = 77 N = 81 26.3 36.3 17.6% (12) 43.9% (34) 54.0% (44) [11.9, 40.6][22.1, 50.6] ¹ITTA: the first 451 subjects enrolled under 52-weekMaintenance protocol in Cohort 1, and who received 8-week UPA 45 mg QDinduction treatment, and at least 1 dose of study drug in theMaintenance Study. ²NRI-C: Non-Responder Imputation [NRI] incorporatingMultiple Imputation [MI] for missing data due to COVID-19. ³95% CI forresponse rate difference (UPA- Placebo) was calculated based on normalapproximation to the binomial distribution. The calculations were basedon non-responder imputation incorporating multiple imputation to handlemissing data due to COVID-19 or non-responder imputation if there wereno missing data due to COVID-19.

Further graphical illustrations of study results with respect to variousendpoints, as well as exposure-response relationships, are provided inFIGS. 34-41E. Notably, a trend was observed for increase in the % ofsubjects achieving each of the evaluated endpoints with increasingupadacitinib C_(avg) (FIGS. 40A-40E), Specifically, an exposure-responsetrend was observed for Week 52 clinical remission, clinical remission &steroid free for ≥90 days (among all subjects in maintenance), endosopicimprovement, endoscopic remission, and HEMI within the 15 mg to 30 mgexposure range. The trend was less apparent for endoscopic remissionthan for the other efficacy endpoints. The efficacy exposure-responsetrends were more clearly observed in subjects who had not achievedclinical remission at the end of induction than in those had achievedremission at the end of induction. Based on preliminaryexposure-response models, 30 mg is predicted to provide ˜8% to 10%greater efficacy for clincial remission, clinical remission & steroidfree for ≥90 days, endosopic improvement, and HEMI compared to 15 mg QDexposures. Without wishing to be bound by theory, the data suggests thatexposures from the 15 mg dose may be adequate in patients who achievedremission at at end of 8-weeks of induction.

Example 21: Clinical Study for Crohn's Disease

This study (Study M14-431) was a Phase 3, randomized, double-blind,placebo-controlled induction study to evaluate the safety and efficacyof upadacitinib (UPA) compared to placebo (PBO) in adult subjects withmoderately to severely active Crohn's disease (CD) who have inadequatelyresponded to or are intolerant to biologic therapy (Bio-IR). This studywas part of an overall induction and maintenance study program asillustrated in FIG. 42 and FIG. 43.

Study Population:

Males and females between 18 and 75 years of age (or minimum age ofadult consent according to local regulations) with a confirmed diagnosisof CD for at least 3 months and moderately to severely active CD whohave inadequately responded to or are intolerant to biologic therapy.Moderately to severely active CD was defined by: Average daily very softor liquid stool frequency (SF)≥4 AND/OR average daily abdominal pain(AP) score ≥2 (values represent the unweighted daily averages of thecorresponding subscores from the Crohn's Disease Activity Index [CDAI]);and Evidence of mucosal inflammation, defined as Simplified EndoscopicScore for CD (SES-CD)≥6 (≥4 for subjects with isolated ileal disease),excluding the presence of narrowing component. Subjects must have had aninadequate response or intolerance to one or more biologic agents for CD(adalimumab, certolizumab, infliximab, ustekinumab and/or vedolizumab).The study allowed enrollment of up to 35% of subjects who havedemonstrated inadequate response or intolerance to 3 or more biologics.

Methodology:

Study M14-431 was a Phase 3, randomized, double-blind,placebo-controlled induction study to evaluate the efficacy and safetyof upadacitinib, an orally administered Janus kinase 1 inhibitor, inadult subjects with moderately to severely active CD who haveinadequately responded to or are intolerant to biologic therapy.Subjects who consent and meet all of the inclusion criteria and none ofthe exclusion criteria were enrolled into this study, which encompassed3 parts: (Part 1) a randomized, double-blind, placebo controlledinduction; (Part 2) an open-label, single-arm active induction; and(Part 3) an Extended Treatment Period for non-responders from Part 1 orPart 2.

Part 1

In Part 1, subjects (n=495) were randomized in a 2:1 ratio toupadacitinib 45 mg once daily (QD) or matching placebo for 12 weeks. Therandomization was stratified by baseline corticosteroid use (yes or no),endoscopic disease severity (SES-CD<15 and ≥15), and number of priorbiologic treatments (>1 and ≤1). The data collected from subjects fromPart 1 was used for the primary efficacy analysis. Visits during thestudy were to occur at Baseline and Weeks 2, 4, 8, and 12/PrematureDiscontinuation (PD) to collect clinical, endoscopic, and laboratoryassessments of disease activity. The last dose of study drug during thisperiod was to be taken the day prior to the Week 12 visit.

At Week 12, subjects achieving clinical response, defined as ≥30%decrease in average daily very soft or liquid SF and/or ≥30% decrease inaverage daily AP score (both not worse than Baseline) were eligible toenter the 52-week, double-blind, maintenance portion of Study M14-430.All subjects who did not achieve clinical response at Week 12 wereenrolled in Part 3 (Extended Treatment Period) and receive double-blindupadacitinib until Week 24/PD. Subjects were not eligible to enter StudyM14-430 until the ileocolonoscopy procedure at Week 12 was completed. Ifthe COVID-19 pandemic precluded a subject from undergoing an endoscopy,the subject was enrolled in Study M14-430 if clinical response wasachieved at Week 12.

Part 2

Part 2 was an open-label portion (open-label cohort) of this study. Onceenrollment in Part 1 was complete, 129 subjects were enrolled in Part 2to receive open-label upadacitinib 45 mg QD for 12 weeks. The objectiveof Part 2 was to have a sufficient number of subjects with clinicalresponse re-randomized in the double-blind, maintenance portion of StudyM14-430, while minimizing unnecessary exposure to placebo. The datacollected from subjects from Part 2 were not part of the primaryefficacy analysis for this study, used descriptive statistics, and werereported separately in the clinical study report. Visits during thestudy occurred at Baseline and Weeks 2, 4, 8, and 12/PD to collectclinical, endoscopic, and laboratory assessments of disease activity. AtWeek 12, subjects achieving clinical response were eligible to enterStudy M14-430. Subjects who did not achieve clinical response at Week 12were eligible to participate in Part 3 (Extended Treatment Period) toreceive open-label upadacitinib 30 mg QD until Week 24/PD.

Part 3

Part 3 was a 12-week Extended Treatment Period consisting of 3 cohortsof subjects who did not achieve clinical response at Week 12 in Part 1or Part 2. Clinical response was defined as ≥30% decrease in averagedaily very soft or liquid SF and/or ≥30% decrease in average daily APand both not greater than Baseline. The objectives of Part 3 were tooffer blinded upadacitinib induction treatment to placebo non-respondersfrom Part 1 and to evaluate delayed clinical response to upadacitinib insubjects who did not initially respond to upadacitinib during Part 1 orPart 2. Part 3 consisted of 3 cohorts, and the treatment assignmentdepended on the treatment received in Part 1 or Part 2, as follows:

-   -   Cohort 1: Subjects who received placebo in Part 1 and did not        achieve clinical response at Week 12 are eligible to receive        double-blind induction treatment with upadacitinib 45 mg QD for        12 weeks (until Week 24).    -   Cohort 2: Subjects who received double-blind upadacitinib in        Part 1 and did not achieve clinical response at Week 12 were        eligible to receive double-blind upadacitinib 30 mg QD for 12        weeks (until Week 24).    -   Cohort 3: Subjects who received open-label upadacitinib during        Part 2 and did not achieve clinical response at Week 12 were        eligible to receive open-label upadacitinib 30 mg QD for 12        weeks (until Week 24).

Subjects in Cohort 1 and 2 remained blinded to treatment to avoidunmasking the treatment received during Part 1. The data collected fromsubjects from Part 3 was not be part of the primary efficacy analysisfor this study, used descriptive statistics, and were reportedseparately in the clinical study report. Subjects were not eligible toenter in Part 3 until the Week 12 endoscopy was completed. If theCOVID-19 pandemic precluded a subject from undergoing an endoscopy, andthe subject had not achieved clinical response, the subject entered Part3 of Study M14-431. Visits occurred at Weeks 16, 20 and 24/PD to collectclinical, endoscopic, and laboratory assessments of disease activity.During Part 3, subjects with persistent symptoms or worsening of CD werediscontinued.

At Week 24, subjects who achieved clinical response were eligible toenter Study M14-430. Subjects were not eligible to enter Study M14-430until the ileocolonoscopy procedure at Week 24 for evaluation of mucosalinflammation was completed. If the COVID-19 pandemic precluded a subjectfrom undergoing an endoscopy, the subject was enrolled in Study M14-430if clinical response was achieved at Week 24. Subjects who do notachieve clinical response at Week 24 were discontinued from StudyM14-431 and received standard of care treatment at the investigator'sdiscretion. Subjects who do not achieve clinical response at Week 24 andall subjects who prematurely discontinued the study had a follow-upvisit 30 days from the last dose of study drug to collect information onnew or ongoing adverse events (AEs) and laboratory assessments. Subjectswere discontinued from the study if they withdrew consent or if theywere deemed unsuitable to continue for any reason by the investigator.The duration of the study was up to 33 weeks, including Screening Period(5 weeks), a 12-week double-blind or open-label cohort Induction Period(Part 1 and Part 2), a 12-week Extended Treatment Period (Part 3), and a30-day follow-up for subjects who do not enroll into Study M14-430.

At the Screening Visit, all subjects were provided with an electronicdiary. Subjects were instructed and trained on how to record CD-relatedsymptoms (including total and very soft and liquid number of stools andabdominal pain), general well-being and use of antidiarrheals on a dailybasis; and use of medications for endoscopy preparation throughout thestudy. The very soft and liquid stools were defined as consistency Type6 or Type 7 based on the Bristol Stool Chart. The diary was reviewed bysite personnel with the subject at each visit and for the assessment ofthe clinical endpoints. At each Study Visit, routine physicalexamination included evaluation of vital signs, extra intestinalmanifestations, and presence or absence of fistulas; calculation of CDAIscore, average daily very soft or liquid SF and average daily AP (SF andAP entries from the most recent 7-day period prior to each study visitwere used); monitoring of AEs; reporting of concomitant medications andlaboratory assessments was performed. The very soft or liquid SF and APscore values represented the unweighted daily averages of thecorresponding subscores from the CDAI. Additionally, subjects completedquality of life (QoL), CD symptoms, symptoms impact on QoL, and workproductivity questionnaires throughout the study. Subjects underwent afull colonoscopy (ileocolonoscopy) for evaluation of mucosalinflammation using the SES-CD. All endoscopies were centrally read todocument eligibility at Screening and for Week 12 and 24/PD assessments.Intestinal biopsies during the endoscopic evaluation were collected forhistologic assessment and exploratory research during endoscopy visitsat Screening, Week 12, and Week 24/PD in approximately 200 subjects(intestinal biopsy substudy). Optional blood samples were collected forexploratory research at Baseline, Week 4, Week 12, and Week 24/PD.Optional stool collections were done at Baseline, Week 4 and Week 12 forexploratory evaluation of biomarkers in approximately 200 subjects(fecal biomarker substudy).

Investigational Product: Upadacitinib (ABT-494); film-coated tabletMode of Administration: Oral, taken at approximately the same time eachday

Doses:

-   -   Part 1: upadacitinib 45 mg QD    -   Part 2: upadacitinib 45 mg QD    -   Part 3: upadacitinib 45 mg QD or upadacitinib 30 mg QD        Reference Therapy: Part 1: placebo

Mode of Administration: Oral

Duration of Treatment: 12 weeks for subjects achieving clinical responseat Week 12; or 24 weeks for subjects who did not achieve clinicalresponse at Week 12.

Diagnosis and Main Criteria for Inclusion/Exclusion

The main criteria for inclusion, and exclusion for the study were asfollows.

Main Inclusion

1. Confirmed diagnosis of CD for at least 3 months prior to Baseline.Appropriate documentation of biopsy results consistent with thediagnosis of CD, as determined by the investigator, were available.2. SES-CD (excluding the presence of narrowing component)≥6 (or ≥4 forsubjects with isolated ileal disease), as confirmed by a central reader.3. Average daily very soft or liquid SF≥4.0 AND/OR average daily APscore ≥2.0 at Baseline.4. Demonstrated an inadequate response or intolerance to one or more ofthe following biologic agents:

-   -   At least one 6-week induction regimen of infliximab (≥5 mg/kg        intravenous [IV] at Baseline and Weeks 2, and 6),    -   At least one 4-week induction regimen of adalimumab (one 160 mg        subcutaneous [SC] dose at Baseline, followed by one 80 mg SC        dose at Week 2 [or one 80 mg SC dose at Baseline, followed by        one 40 mg SC dose at Week 2, in countries where this dosing        regimen was approved])    -   At least one 4-week induction regimen of certolizumab pegol (400        mg SC at Baseline and Weeks 2, and 4)    -   At least one 6-week induction regimen of vedolizumab (300 mg IV        at Baseline and Weeks 2, and 6)    -   At least one 8-week induction regimen of ustekinumab P60 mg (≤55        kg) or 390 mg (>55 to ≤85 kg) or 520 mg (>85 kg) W, followed by        90 mg SC at Week 8]    -   Recurrence of symptoms during scheduled maintenance dosing        following prior clinical benefit of the above biologics    -   Intolerance to a biologic may include, but not limited to        infusion-related reaction, rash, serum sickness, anaphylaxis,        elevated liver enzymes, demyelination, congestive heart failure,        infection. Demonstration of intolerance requires no minimum dose        or duration of use.

Main Exclusion

1. Subject with a current diagnosis of ulcerative colitis orindeterminate colitis.

Concomitant Medications and Treatments

2. Subject on CD related antibiotics who:

-   -   had not been on stable doses of these medications for at least        14 days prior to Baseline, or    -   had discontinued these medications within 14 days of Baseline.        3. Subject on oral aminosalicylates who:    -   had not been on stable doses of these medications for at least        14 days prior to Baseline, or    -   had discontinued these medications within 14 days of Baseline.        4. Subject on corticosteroids who meet the following:    -   prednisone or equivalent dose >30 mg/day; or    -   budesonide >9 mg/day; or    -   had not been on the current course for at least 14 days prior to        Baseline and on a stable dose for at least 7 days prior to        Baseline.

5. Subject on MTX who:

-   -   had not been on the current course for ≥42 days prior to        Baseline, and    -   had not been on a stable dose for ≥28 days prior to Baseline        6. Infection(s) requiring treatment with intravenous (IV)        anti-infectives within 30 days prior to the Baseline Visit or        oral/intramuscular (IM) anti-infectives within 14 days prior to        the Baseline Visit.        7. Subject requiring or receiving any parenteral nutrition        and/or exclusive enteral nutrition.        8. Subject who received oral or parenteral traditional Chinese        medicines within 30 days prior to Baseline.        9. Subject who received any live vaccination within 30 days (or        longer if required locally [e.g., 8 weeks for Japan]) prior to        Baseline, or who were expected to need live vaccination during        study participation including at least 30 days (longer if        required locally [e.g., 8 weeks for Japan]) after the last dose        of study drug.        10. Subject who received cyclosporine, tacrolimus, mycophenolate        mofetil, or thalidomide within 30 days prior to Baseline.        11. Subject who received azathioprine (AZA) or 6-mercaptopurine        (6-MP) within 10 days of Baseline.        12. Subject who received fecal microbial transplantation within        30 days prior to Baseline.        13. Subject who received nonsteroidal anti-inflammatory drugs        (NSAIDs) within 7 days prior to Baseline, except topical NSAIDs        and low dose aspirin for cardiovascular protection.        14. Systemic use of known strong cytochrome P450 (CYP)3A        inhibitors or strong CYP3A inducers from Screening through the        end of the study. The most common strong CYP3A inhibitors        include: Boceprevir, Cobicistat, Clarithromycin, Conivaptan,        Grapefruit (fruit or juice), Indinavir, Itraconazole,        Ketoconazole, Lopinavir/Ritonavir, Mibefradil, Nefazodone,        Nelfinavir, Posaconazole, Ritonavir, Saquinavir, Telaprevir,        Telithromycin, Troleandomycin, and Voriconazole. The most common        strong CYP3A inducers include: Avasimibe, Carbamazepine,        Phenytoin, Rifampin (rifampicin), Rifapentine, and St. John's        Wort.        15. Subject who received any of the following agents:    -   adalimumab, certolizumab, golimumab, infliximab, natalizumab,        vedolizumab        within 8 weeks prior to Baseline; or    -   ustekinumab within 12 weeks prior to Baseline.        -   Note: If there was proper documentation of an undetectable            drug level measured by a commercially available assay for            any of the approved biologics above, there was no minimum            washout prior to Baseline.    -   any investigational agent within 30 days or 5 half-lives prior        to Baseline, whichever was longer, or was currently enrolled in        another interventional study.        16. Subject with previous exposure to a JAK inhibitor (e.g.,        tofacitinib, baricitinib, filgotinib) within 30 days from        Baseline. Note: Subjects who received a JAK inhibitor prior to        study entry may be enrolled if they have not had inadequate        response or loss of response.        17. Subject was taking both oral budesonide (or oral        beclomethasone) and oral prednisone (or equivalent)        simultaneously, with the exception of topical or inhalers within        14 days prior to Screening or during the Screening Period.        18. Subject received IV corticosteroids within 14 days prior to        Screening or during the Screening Period.        19. Subject received therapeutic enema or suppository (i.e.,        rectal aminosalicylates/corticosteroids), other than required        for endoscopy, within 14 days prior to endoscopy used for        Screening or during the Screening period.        20. Subject received apheresis (e.g., Adacolumn apheresis)        within 60 days prior to Screening or during the Screening        Period.        21. Subject used cannabis, either recreational or for medical        reasons, within 14 days prior to Baseline or any history of        clinically significant (per investigator's judgment) drug or        alcohol abuse in the last 6 months.        22. Subject received stem cell transplantation (except for local        stem cell therapy for complex perianal fistula).        23. Subject was a previous recipient of an organ transplant        which requires continued immunosuppression.

CD Related

24. Subject with the ongoing following known complications of CD:

-   -   abscess (abdominal or peri-anal)    -   symptomatic bowel strictures    -   >2 entire missing segments of the following 5 segments: terminal        ileum, right colon, transverse colon, sigmoid and left colon,        and rectum    -   fulminant colitis    -   toxic megacolon    -   or any other manifestation that might require surgery while        enrolled in the study.        25. Subject with ostomy or ileoanal pouch        26. Subject diagnosed with conditions that could interfere with        drug absorption including but not limited to short gut or short        bowel syndrome.        27. Subject with surgical bowel resection within the past 3        months prior to Baseline, or a history of >3 bowel resections

Safety

28. Subject with positive Clostridium difficile (C. difficile) toxinstool assay during Screening.29. Any active, chronic or recurrent infection that, based on theinvestigator's clinical assessment, made the subject an unsuitablecandidate for the study, including hepatitis B virus (HBV) or hepatitisC virus (HCV), recurrent or disseminated (even a single episode) herpeszoster, disseminated (even a single episode) herpes simplex, or HIVinfection. Active HBV, HCV and HIV are defined as:

-   -   HBV: hepatitis B surface antigen (HBs Ag) positive (+) or        detected sensitivity on the HBV-deoxyribonucleic acid (DNA)        polymerase chain reaction (PCR) qualitative test for hepatitis B        core antibody (HBc Ab) positive (+) subjects;    -   HCV: HCV ribonucleic acid (RNA) detectable in any subject with        anti-HCV antibody (HCV Ab);    -   HIV: confirmed positive anti-HIV antibody (HIV Ab) test;    -   Confirmed COVID-19: the Baseline visit must be at least 14 days        from onset of signs/symptoms or positive SARS-CoV-2 test,        symptomatic subjects must have recovered, defined as resolution        of fever without use of anti-pyretics and improvement in        symptoms;    -   Suspected COVID-19: subjects with signs/symptoms suggestive of        COVID-19, known exposure, or high risk behavior should undergo        molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection        or must be asymptomatic for 14 days from a potential exposure.        30. Subject had active TB or meets TB exclusionary parameters        31. History of any malignancy except for successfully treated        nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of        the cervix.        32. Prior or current gastrointestinal dysplasia, other than        completely removed lowgrade dysplastic lesions in any biopsy        performed during or before the Screening endoscopy.        33. History of gastrointestinal perforation (other than        appendicitis or mechanical injury), diverticulitis or        significantly increased risk for gastrointestinal perforation        per investigator judgment.        34. Female who was pregnant, breastfeeding, or was considering        becoming pregnant during the study or within 30 days after the        last dose of study drug.        35. History of an allergic reaction or significant sensitivity        to constituents of the study drug (and its excipients) and/or        other products in the same.        36. Laboratory values meeting the following criteria within the        Screening period prior to the first dose of study drug:    -   Serum aspartate transaminase (AST) or alanine transaminase        (ALT)>2.0×upper limit of the reference range (ULN)    -   Total white blood cell count <2500/μL,    -   Estimated glomerular filtration rate by simplified 4-variable        Modification of Diet in Renal Disease (MDRD) formula <30        mL/min/1.73 m2    -   Hemoglobin <9 g/dL;    -   Platelet count <100,000/μL    -   Absolute neutrophil count <1200/μL    -   Absolute lymphocyte count <750 μL.        37. Any of the following cardiovascular conditions or thrombotic        conditions within 6 months prior to the study)    -   cerebrovascular accident, myocardial infarction, coronary        stenting;    -   current uncontrolled hypertension as defined by a confirmed        systolic blood pressure (BP) >160 mmHg or diastolic BP >100        mmHg;    -   prior history of thrombotic events including deep venous        thrombosis and pulmonary embolism;    -   known inherited conditions that predispose to        hypercoagulability.        38. History of clinically significant medical conditions or any        other reason that in the opinion of the investigator would have        interfered with the subject's participation in this study or        would have made the subject an unsuitable candidate to receive        study drug or would have put the subject at risk by        participating in the study.        39. For Japan subjects only: positive result of beta-D-glucan,        or two consecutive indeterminate results of beta-D-glucan during        the Screening Period.        Concomitant CD-Related Medications (Antibiotics,        Aminosalicylates, and/or Methotrexate)

All subjects receiving a stable dose of CD-related antibiotics,aminosalicylates, or methotrexate (MTX) at Baseline maintained theirconcomitant treatments without dose changes through the end of thestudy. Initiating and/or changing doses of these medications wasprohibited during the study. Doses of CD-related antibiotics,aminosalicylates, or MTX were decreased only in the event ofmoderate-to-severe treatment related toxicities. Setons were authorizedas concomitant therapy in subjects with perianal fistulas and documentedin the eCRF under concomitant medications.

Concomitant Corticosteroids

Subjects who entered the study on oral corticosteroids were not allowedto change the corticosteroid dose during the first 4 weeks of theinduction treatment period. Doses of corticosteroids were decreasedduring the first 4 weeks only in the event of moderate-to-severetreatment related toxicities. At Week 4, subjects had theircorticosteroid dose reduced according to a tapering schedule asdescribed. At Week 4, subjects who were on prednisone (or oralequivalent) or oral budesonide had their corticosteroid dose tapered,according to the tapering schedule. Subjects who did not achieveclinical response at Week 12 in Part 1 or Part 2, and enter Part 3without having completed the steroid taper resumed the corticosteroidtaper at Week 16, according to the tapering schedule. Initiating locallyacting (rectal or suppository) or systemic corticosteroids for anyreason was prohibited during the induction treatment period and wasconsidered a protocol deviation and was discussed with the TA MD. Use ofinhaled or topical (except rectal or suppository) corticosteroids wasnot restricted. Subjects were not allowed to be on both budesonide (forCD disease) and prednisone (or equivalent) simultaneously.

Biologic Therapies

Subjects must have discontinued any biologic therapy prior to the firstdose of study drug as specified in the washout procedures. Therapiesincluding but not limited to the following biologic therapies wereprohibited medications during the study:

-   -   Adalimumab    -   Etanercept    -   Infliximab    -   Abatacept    -   Anakinra    -   Rituximab    -   Natalizumab    -   Tocilizumab    -   Golimumab    -   Certolizumab    -   Ustekinumab    -   Belimumab    -   Secukinumab    -   Vedolizumab

Strong CYP3A Inhibitors or Inducers

Systemic use of known strong CYP3A inhibitors or strong CYP3A inducerswas excluded from the Screening Visit through the end of the study.

Other medications prohibited during the study

-   -   JAK inhibitors (e.g., tofacitinib [Xeljanz®])    -   Cyclosporine, tacrolimus, thalidomide, mycophenolate mofetil,        AZA, or 6-MP.    -   NSAIDs (except topical NSAIDs and the use of low dose aspirin        for cardiovascular protection).    -   Rectal therapy with any therapeutic enemas or suppositories,        with the exception of those required for endoscopy.    -   Any parenteral nutrition and exclusive enteral nutrition.    -   Cytapheresis treatment (granulocytapheresis, etc.) (in Japan and        China only).    -   Cannabis

Criteria for Evaluation Outcomes and Questionnaires

The following outcomes and questionnaires were completed at the timepoints as indicated.

-   -   Inflammatory Bowel Disease Questionnaire (IBDQ)    -   Work Productivity and Activity Impairment Questionnaire        (WPAI)-CD    -   Crohn's Symptoms Severity Questionnaire (CSS)    -   Short Form-36 (SF-36)    -   European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)    -   Functional Assessment of Chronic Illness Therapy-Fatigue        (FACIT-F)    -   Patient Global Impression of Change (PGIC)    -   Patient Global Impression of Severity (PGI-S)    -   Bristol Stool Chart

Primary/Secondary Efficacy Endpoints and the Overall Type-I ErrorControl

The study had different sets of primary and secondary endpoints forEU/EMA (Table 35) or for US/FDA (Table 36) regulatory purposes.Endpoints and the corresponding overall type-I error control details areprovided below and in FIG. 26.

Endpoint Definitions

-   -   Clinical remission per patient reported outcomes (PROs): Average        daily very soft or liquid SF≤2.8 AND average daily AP score ≤1.0        and both not greater than baseline    -   Clinical remission per CDAI: CDAI<150    -   Steroid-Free Clinical Remission per CDAI/PRO: Discontinuation of        corticosteroid use and clinical remission per CDAI/PRO at Week        12, among subjects taking corticosteroids at Baseline    -   Clinical response 100 (CR-100): decrease of ≥100 points in CDAI        from Baseline    -   Enhanced Clinical Response: ≥60% decrease in average daily very        soft or liquid SF and/or ≥35% decrease in average daily AP score        and both not greater than baseline, or clinical remission    -   Endoscopic remission: SES-CD≤4 and at least 2-point reduction        from Baseline and no subscore >1 in any individual variable, as        scored by central reviewer    -   Endoscopic response: Decrease in SES-CD>50% from Baseline of the        induction study (or for subjects with an SES-CD of 4 at Baseline        of the induction study, at least a 2-point reduction from        Baseline), as scored by central reviewer.

TABLE 35 Primary and Key Secondary Endpoints for EU/EMA RegulatoryPurposes Endpoint Overall Type-I Error Control Co-Primary Endpoints:Co-primary endpoints must be Achievement of clinical remission per PROsat Week 12 achieved statistical significance Achievement of endoscopicresponse at Week 12 simultaneously (alpha = 0.05). Key SecondaryEndpoint in Ranked Order: Fixed sequential testing procedure: a 1.Achievement of clinical remission per CDAI at Week 12 secondary endpointwas tested only 2. Achievement of clinical remission per PROs at Week 4if the co-primary endpoints and all 3. Achievement of endoscopicremission at Week 12 higher-ranked secondary endpoints 4. Achievement ofsteroid-free clinical remission per PROs achieved statisticalsignificance at Week 12, among subjects taking corticosteroids for CD(alpha = 0.05). at Baseline 5. Change from Baseline in FunctionalAssessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score atWeek 12 6. Change from Baseline in Inflammatory Bowel DiseaseQuestionnaire (IBDQ) total score at Week 12 Key Secondary Endpointsunder Holm Procedure: Achievement of CR-100 at Week 2 Holm testingprocedure: only if all Achievement of CR-100 at Week 12 co-primaryendpoints and secondary Occurrence of hospitalizations due to CD duringPart 1 endpoints 1-6 achieved statistical Achievement of resolution ofextra-intestinal significance (alpha = 0.05). manifestations (EIMs) atWeek 12, among subjects with EIMs at Baseline

TABLE 36 Primary and Secondary Endpoints for US/FDA Regulatory PurposesEndpoint Overall Type-I Error Control Co-Primary Endpoints: Co-primaryendpoints must be Achievement of clinical remission per CDAI at Week 12achieved statistical significance Achievement of endoscopic response atWeek 12 simultaneously (alpha = 0.05). Key Secondary Endpoint in RankedOrder: Fixed sequential testing procedure: a 1. Achievement of clinicalremission per PROs at Week 12 secondary endpoint was tested only 2.Achievement of endoscopic remission at Week 12 if the co-primaryendpoints and all 3. Achievement of steroid-free clinical remission perCDAI higher-ranked secondary endpoints at Week 12, among subjects takingcorticosteroids for achieved statistical significance CD at Baseline(alpha = 0.05). 4. Change from Baseline in FACIT-F total score at Week12 5. Change from Baseline in IBDQ total score at Week 12 Key SecondaryEndpoints under Holm Procedure: Achievement of CR-100 at Week 2 Holmtesting procedure: only if all Achievement of CR-100 at Week 12co-primary endpoints and secondary Achievement of clinical remission perCDAI at Week 4 endpoints 1-5 achieved statistical Occurrence ofhospitalizations due to CD during Part 1 significance (alpha = 0.05).Achievement of resolution of extra-intestinal manifestations (EIMs) atWeek 12, among subjects with EIMs at Baseline

Pharmacokinetic Variables

Upadacitinib plasma concentrations were determined from samplescollected at each visit beginning at Week 2. Blood samples at the Week 4visit were collected prior to dosing if possible. For all other visits,blood samples were collected at any time during the visit. A non-linearmixed effects modeling approach were used to estimate the populationcentral values and the empirical Bayesian estimates of the individualvalues of upadacitinib oral clearance (CL/F) and volume of distribution(V/F). Additional parameters where estimated when useful in theinterpretation of the data.

Safety Variables

Safety analyses were performed on the safety set, which included allsubjects who receive at least one dose of study drug. The incidence ofAEs, changes in vital signs, physical examination results, and clinicallaboratory data were assessed throughout the study. Electrocardiogramswere performed at screening, and at the end of each Part 1, 2, 3 of thestudy. AEs and laboratory data, when available, were graded as describedin the National Cancer Institute Common Terminology Criteria for AdverseEvents and summarized accordingly. An external, independent DataMonitoring Committee were responsible for monitoring unblended safetydata and alerting AbbVie to possible safety concerns related to theconduct of the study.

Statistical Methods Efficacy

The co-primary endpoints were the proportion of subjects with clinicalremission per PROs (EU/EMA) or clinical remission per CDAI (US/FDA) atWeek 12 and the proportion of subjects with endoscopic response at Week12. This study evaluated one induction dose of upadacitinib 45 mg QD.Efficacy analysis was based on all intent-to-treat (ITT) subjects. TheITT analysis set included all randomized subjects who had taken at leastone dose of study drug in the double-blind induction period from Part 1.The comparison between treatment groups on the co-primary efficacyendpoints was performed using the Cochran-Mantel-Haenszel (CMH) test andstratified by Baseline corticosteroid use (yes or no), endoscopicdisease severity (SES-CD<15 and ≥15), and number of prior biologics used(>1 and ≤1). Both of the co-primary efficacy endpoints were tested attwo-sided significance level of 0.05. A CMH-based, two-sided 95%confidence interval for the difference between treatment groups wascalculated. If the average daily SF or average daily AP score (EU/EMA)or CDAI (US/FDA) data at Week 12 were missing, the non-responderimputation approach was applied for the clinical remission per PROs andclinical remission per CDAI endpoints, respectively. Subjects whodiscontinued prior to Week 12 for any reason were considered as“not-achieved” for clinical remission or endoscopic response endpoints.A multiple testing procedure was used to provide strong control of thetype 1 error rate at alpha=0.05 (2-sided) across analyses with respectto the co-primary endpoints, and ranked secondary endpoints.Specifically, testing utilized a sequence of hypothesis testing for theco-primary endpoints followed by the ranked secondary endpoints, andbegan with testing co-primary endpoints using a of 0.05 (2-sided). Ifboth co-primary endpoints achieved statistical significance, continuedtesting followed a pre-specified weight of α-allocation betweenindividual hypotheses as well as between families of hypotheses. Thedetails of the testing procedure are specified and documented in thestatistical analysis plan (SAP). In general, continuous secondaryefficacy variables with repeated measurements were analyzed using aMixed Effect Repeated Measure (MMRM) model. Continuous secondaryefficacy variables which were collected at only one post-baseline visit(such as SES-CD) were analyzed using an Analysis of Covariance (ANCOVA)model. Categorical secondary efficacy variables were analyzed using theCMH test controlling for stratification variables. NRI for missing datawere used for categorical secondary endpoints.

Pharmacokinetics

A non-linear mixed-effects modeling approach were used to estimate thepopulation central values and the empirical Bayesian estimates of theindividual values for upadacitinib oral clearance and volume ofdistribution. Additional parameters were estimated when useful in theinterpretation of the data.

Safety

AEs, laboratory data, and vital signs were the primary safety parametersin this study. All safety comparisons were performed between treatmentgroups using the safety set. Treatment-emergent AEs were defined asevents that began or worsened either on or after the first dose of thestudy drug and within 30 days after the last dose of the study drug forsubjects who did not participate in Study M14-430, or within 30 daysafter the last dose of study drug in Study M14-431 or first dose ofstudy drug in Study M14-430 if the subject enrolled in Study M14-430,whichever came first. An overview of treatment-emergent AEs, includingAEs of special interest, AEs leading to death, AEs leading to PD, AEs byMedical Dictionary for Drug Regulatory Activities preferred term andsystem organ class, AEs by maximum relationship to study drug, and AEsby maximum severity was summarized by number and percentage. Changes inlaboratory data were described using statistical characteristics andcomparison between treatment groups performed using a one-way Analysisof Variance. In addition, shift tables and listings were provided forabnormal values, whereby the normal range of the analyzing laboratorywas used. Vital signs were analyzed similarly.

Primary Approach to Handle Missing Data

For categorical variables, the primary approach to handle missing datawas Non-Responder Imputation (NRI) incorporating Multiple Imputation(MI) for missing data due to COVID-19 (NRI-C). For continuous variables,missing data were handled by Mixed-effect Model Repeat Measurement(MMRM).

Results Study Summary

This study comprised a 12-week Induction Period (FIG. 45), an option ofa 12-week Extended Treatment Period (FIG. 46), and a 30-day Follow-upPeriod for subjects who did not roll over to the Maintenance StudyM14-430. Subjects which entered the study with background corticosteroidhad their corticosteroid dose reduced according to theprotocol-specified tapering schedule. The clinical response in FIG. 45and FIG. 46 was defined as ≥30% decrease in average daily very soft orliquid SF and/or ≥30% decrease in average daily AP score, with both SFand AP not worse than Baseline. With reference to FIGS. 45 and 46, theInduction and Extended Treatment Periods were designed as follows:

Induction Period (Baseline to Week 12, (FIG. 27)):

At Baseline, eligible subjects were enrolled to a 12-week InductionPeriod (double-blinded, placebo (PBO)-controlled [Part 1] or single-arm,open-label [Part 2]). Part 1 was a randomized, double-blind,PBO-controlled part with 12-week induction treatment. Subjects in Part 1were randomized to either UPA 45 mg QD or matching PBO in a 2:1 ratio.The randomization was stratified by corticosteroid use (yes or no),endoscopic disease severity as evaluated by the Simplified EndoscopicScore for Crohn's Disease (SES-CD; <15 or ≥15), and the number of priorbiologic treatments (>1 or ≤1). All primary and secondary efficacyendpoints were analyzed in the ITT1 Population, which was defined as allrandomized subjects with at least one dose of study drug in Part 1. Toensure sufficient sample size in the downstream Maintenance StudyM14-430, additional subjects were enrolled to a single-arm, open-labelarm to receive UPA 45 mg QD 12-week induction treatment (Part 2).

Extended Treatment Period (Week 12 to Week 24, (FIG. 28):

At Week 12, subjects who achieved the clinical response were rolled overto the Maintenance Study M14-430, whereas subjects who did not achievethe clinical response entered an Extended Treatment Period (Part 3).Specifically, subjects who received PBO in Part 1 received UPA 45 mg QD(Cohort 1), whereas subjects who received UPA 45 mg QD in Part 1received UPA 30 mg QD (Cohort 2). Treatments in Cohort 1 and 2 weregiven in a blinded fashion. Subjects who received UPA 45 mg QD in Part 2received open-label UPA 30 mg QD (Cohort 3).

Demographic, Baseline Characteristics, and Subject Disposition

A total of 495 subjects were randomized (171 in PBO and 324 in UPA 45mg) in Part 1, and all were treated. There were 440 (88.9%) subjects whocompleted the 12-week induction period of study drug in Part 1 (Table37). Demographics and baseline characteristics were generally balancedbetween treatment groups (Table 38). Subject disposition in Part 2 and 3are presented in Table 39.

TABLE 37 Subject Disposition in Part 1 Subject PBO UPA 45 mg TotalDisposition, n (%) (N = 171) (N = 324) (N = 495) Randomized 171 (100)324 (100) 495 (100) Treated 171 (100) 324 (100) 495 (100) Completed theStudy Drug in Part 1 149 (87.1) 291 (89.8) 440 (88.9) Discontinued StudyDrug during Part 1 (Primary 22 (12.9) 33 (10.2) 55 (11.1) Reasons)Adverse event 5 (2.9) 16 (4.9) 21 (4.2) Withdrawal by subject 8 (4.7) 7(2.2) 15 (3.0) Lost to follow-up 0 1 (0.3) 1 (0.2) Lack of efficacy 8(4.7) 5 (1.5) 13 (2.6) COVID-19 infection 0 0 0 COVID-19 logisticalrestrictions 0 0 0 Other 1 (0.6) 4 (1.2) 5 (1.0) Discontinued Study Drugduring Part 1 (All 22 (12.9) 33 (10.2) 55 (11.1) Reasons) Adverse event7 (4.1) 18 (5.6) 25 (5.1) Withdrawal by subject 8 (4.7) 7 (2.2) 15 (3.0)Lost to follow-up 0 1 (0.3) 1 (0.2) Lack of efficacy 8 (4.7) 5 (1.5) 13(2.6) COVID-19 infection 0 0 0 COVID-19 logistical restrictions 0 0 0Other 2 (1.2) 6 (1.9) 8 (1.6)

TABLE 38 Demographics and Baseline Disease Characteristics Part 1 Part 2Demographic and Double-Blind Open-Label Baseline Characteristics, PBOUPA 45 mg UPA 45 mg mean (SD) or n (%) (N = 171) (N = 324) (N = 129)Female 75 (43.9) 155 (47.8) 60 (46.5) Age (years) 37.5 (12.12) 38.4(13.71) 39.1 (12.05) Weight (kg) 69.8314 (19.3010) 69.6181 (18.7540)74.3817 (18.6870) Body Mass Index (kg/M{circumflex over ( )}2) 23.901(6.1894) 24.164 (5.9763) 25.263 (5.9620) Race White 126 (73.7) 230(71.0) 113 (87.6) Black or African American 6 (3.5) 19 (5.9) 5 (3.9)Asian 38 (22.2) 69 (21.3) 11 (8.5) American Indian/Alaska Native 1 (0.6)1 (0.3) 0 Multiple 0 5 (1.5) 0 Disease Duration (years) 10.9361 (7.9930)12.0521 (9.5409) 11.4030 (8.2380) CD-Related Corticosteroid Use Yes 60(35.1) 108 (33.3) 46 (35.7) No 111 (64.9) 216 (66.7) 83 (64.3) Number ofPrior Biologic Treatments  ≤1 68 (39.8) 126 (38.9) 44 (34.1)   2 55(32.2) 92 (28.4) 30 (23.3)  ≥3 48 (28.1) 106 (32.7) 55 (42.6) SES-CDCategory  <15 94 (55.0) 181 (55.9) 69 (53.5) ≥15 77 (45.0) 143 (44.1) 60(46.5) SES-CD 14.9 (7.75) 15.2 (7.82) 14.9 (6.78) CDAI Score 308.08(84.267) 306.64 (89.423) 313.50 (99.237) Average Very Soft/Liquid Stool6.0929 (3.3355) 5.7299 (3.3603) 5.9103 (3.4082) Frequency AverageAbdominal Pain 1.7955 (0.6849) 1.8508 (0.6913) 1.9181 (0.7218) Hs-CRP(mg/L) Mean (SD) 18.983 (24.0176) 20.860 (25.9725) 17.994 (20.2435)Median (range) 9.470 (0.41, 126.00) 10.500 (0.20, 144.00) 12.600 (0.21,122.00) Fecal Calprotectin (μg/g) Mean (SD) 2184.7 (3148.34) 2286.6(3880.36) 2406.4 (3351.27) Median (range) 1115.0 (30, 19104) 1041.0 (30,28800) 1486.0 (30, 28800)

TABLE 39 Subject Disposition in Part 2 and Part 3 Part 2 Part 3 OL DBPBO/ DB UPA 45 mg/ OL UPA 45 mg/ Subject UPA 45 mg UPA 45 mg UPA 30 mgUPA 30 mg Disposition, n (%) (N = 129) (N = 78) (N = 69) (N = 14)Treated 129 (100) 78 (100) 69 (100) 14 (100) Completed the Study Drug122 (94.6) 67 (85.9) 51 (73.9) 8 (57.1) Discontinued Study Drug (Primary7 (5.4) 11 (14.1) 18 (26.1) 6 (42.9) Reasons) Adverse event 2 (1.6) 7(9.0) 5 (7.2) 0 Withdrew consent 3 (2.3) 0 5 (7.2) 0 Lost to follow-up 00 0 1 (7.1) Lack of efficacy 1 (0.8) 3 (3.8) 6 (8.7) 4 (28.6) COVID-19infection 0 0 0 0 COVID-19 logistical restrictions 0 0 1 (1.4) 0 Other 1(0.8) 1 (1.3) 1 (1.4) 1 (7.1) Discontinued Study Drug (All Reasons) 7(5.4) 11 (14.1) 18 (26.1) 6 (42.9) Adverse event 2 (1.6) 8 (10.3) 6(8.7) 1 (7.1) Withdrew consent 3 (2.3) 0 6 (8.7) 0 Lost to follow-up 0 00 2 (14.3) Lack of efficacy 2 (1.6) 3 (3.8) 7 (10.1) 4 (28.6) COVID-19infection 0 0 0 0 COVID-19 logistical restrictions 0 0 1 (1.4) 0 Other 1(0.8) 2 (2.6) 2 (2.9) 1 (7.1)

Clinical Results

In patients with moderately to severely active Crohn's disease who hadfailed one or more biologics, the study demonstrated the superiority ofUPA 45 mg QD vs. placebo as induction treatment for 12 weeks inco-primary endpoints (clinical remission per CDAI, clinical remissionper PRO and endoscopic response) for both EU/EMA and US/FDA regulatorypurposes with p<0.0001 (FIG. 47). In addition, 8 out of 10 key secondaryendpoints also achieved statistical significance. Efficacy wasdemonstrated across clinical, endoscopic, steroid-free, fatigue, andquality of life measures. Rapid onset of action was observed(achievement of clinical response and/or remission). Specifically,clinical remission per CDAI and PRO measures was observed as early asweek 2 (FIG. 48 and FIG. 49, respectively). Endoscopic response andendoscopic remission were achieved at week 12 (FIG. 50). Steroid-freeclinical remission with both CDAI and PRO measures was achieved at theend of induction treatment (week 12) with upadacitinib (FIG. 51).Efficacy results and associated statistical measures for primary and keysecondary endpoints are shown in Table 40 (EU/EMA) and Table 41(US/FDA). Consistent efficacy results of co-primary endpoints wereobserved in the sensitivity analyses, as shown in Table 42. Selectedefficacy endpoints at the end of each study part are summarized in Table43.

TABLE 40 Primary and Key Secondary Endpoints for EU/EMA RegulatoryPurposes (ITT1 Population) PBO UPA 45 mg Adj. Diff Endpoint (N = 171) (N= 324) [95% CI] p-value¹ Co-Primary Endpoints Clinical remission perPROs at Week 12; n (%) 24 (14.0) 129 (39.8) 25.9 [18.7, 33.1] <.0001^(S)Endoscopic response at Week 12; n (%) 6 (3.5) 112 (34.6) 31.2 [25.5,37.0] <.0001^(S) Key Secondary Endpoints Clinical remission per CDAI atWeek 12; n (%) 36 (21.1) 126 (38.9) 17.9 [10.0, 25.8] <.0001^(S)Clinical remission per PROs at Week 4; n (%) 16 (9.4) 105 (32.4) 23.3[16.6, 29.9] <.0001^(S) Endoscopic remission at Week 12; n (%) 4 (2.3)62 (19.1) 16.8 [12.0, 21.6] <.0001^(S) Steroid-free & clinical remissionper PROs at (N = 60) (N = 108) 30.2 [19.4, 41.0] <.0001^(S) Week 12,among patients with corticosteroids for 4 (6.7) 40 (37.0) CD atBaseline; n (%) FACIT-F total score at Week 12; LS Mean Change (N = 129)(N = 278) 7.5 [5.2, 9.8] <.0001^(S) (SE) 3.9 (0.97) 11.4 (0.69) IBDQtotal score at Week 12; LS Mean Change (N = 130) (N = 280) 24.3 [17.2,31.5] <.0001^(S) (SE) 21.6 (3.02) 46.0 (2.14) CR-100 at Week 2; n (%) 21(12.4) 107 (33.2) 20.7 [13.7, 27.8] <.0001^(S) CR-100 at Week 12; n (%)47 (27.5) 164 (50.5) 22.8 [14.4, 31.2] <.0001^(S) Occurrence ofhospitalizations due to CD in Part 15 (8.8) 20 (6.2) -2.6 [-7.6, 2.4]0.2834^(NS) 1; n (%) Resolution of EIMs at Week 12, among pts with (N =60) (N = 131) 11.5 [-1.5, 24.4] 0.0833^(NS) EIMs at Baseline; n (%) 13(21.7) 43 (32.8) Among intent-to-treat population for Part 1 (ITT1),which includes all subjects who are randomized and received at least onedose of study drag in the 12-Week Induction Period. Missing data wereimputed using Non-Responder Imputation (NRI) while incorporatingMultiple Imputation to handle missing data due to COVID-19 (NRI-C) forcategorical endpoints, and using Mixed-Effect Model Repeat Measurement(MMRM) for continuous endpoints. ¹P-value for treatment differencebetween UPA 45 mg and PBO, using CMH test for categorical endpoints andusing MMRM for continuous endpoints, controlling for stratificationfactors. PBO: Placebo UPA: Upadacitinib CI: Confidence Interval EIM:extra-intestinal manifestations S/NS: Achieved/not achieved statisticalsignificance according to the testing strategy for overall type-I errorcontrol as indicated.

TABLE 41 Primary and Key Secondary Endpoints for US/FDA RegulatoryPurposes (ITT1 Population) PBO UPA 45 mg Adj. Diff Endpoint (N = 171) (N= 324) [95% CI] p-value¹ Co-Primary Endpoints Clinical remission perCDAI at Week 12; n (%) 36 (21.1) 126 (38.9) 17.9 [10.0, 25.8] <.0001^(S)Endoscopic response at Week 12; n (%) 6 (3.5) 112 (34.6) 31.2 [25.5,37.0] <.0001^(S) Key Secondary Endpoints Clinical remission per PROs atWeek 12; n (%) 24 (14.0) 129 (39.8) 25.9 [18.7, 33.1] <.0001^(S)Endoscopic remission at Week 12; n (%) 4 (2.3) 62 (19.1) 16.8 [12.0,21.6] <.0001^(S) Steroid-free & clinical remission per CDAI at (N = 60)(N = 108) 22.5 [11.1, 34.0] <.0001^(S) Week 12, among pts withcorticosteroids for CD at 7 (11.7) 37 (34.3) Baseline; n (%) FACIT-Ftotal score at Week 12; LS Mean Change (N = 129) (N = 278) 7.5 [5.2,9.8] <.0001^(S) (SE) 3.9 (0.97) 11.4 (0.69) IBDQ total score at Week 12;LS Mean Change (N = 130) (N = 280) 24.3 [17.2, 31.5] <.0001^(S) (SE)21.6 (3.02) 46.0 (2.14) CR-100 at Week 2; n (%) 21 (12.4) 107 (33.2)20.7 [13.7, 27.8] <.0001^(S) CR-100 at Week 12; n (%) 47 (27.5) 164(50.5) 22.8 [14.4, 31.2] <.0001^(S) Clinical remission per CDAI at Week4; n (%) 30 (17.7) 96 (29.6) 12.1 [4.7, 19.5] <.0001^(S) Occurrence ofhospitalizations due to CD in Part 1; 15 (8.8) 20 (6.2) −2.6 [−7.6, 2.4]0.2834^(NS) n (%) Resolution of EIMs at Week 12, among pts with (N = 60)(N = 131) 11.5 [−1.5, 24.4] 0.0833^(NS) EIMs at Baseline; n (%) 13(21.7) 43 (32.8) Among intent-to-treat population for Part 1 (ITT1),which includes all subjects who are randomized and received at least onedose of study drag in the 12-Week Induction Period. Missing data wereimputed using Non-Responder Imputation (NRI) while incorporatingMultiple Imputation to handle missing data due to COVID-19 (NRI-C) forcategorical endpoints, and using Mixed-Effect Model Repeat Measurement(MMRM) for continuous endpoints ¹P-value for treatment differencebetween UPA 45 mg and PBO, using CMH test for categorical endpoints andusing MMRM for continuous endpoints, controlling for stratificationfactors. PBO: Placebo UPA: Upadacitinib CI: Confidence Interval EIM:extra-intestinal manifestations S/NS: Achieved/not achieved statisticalsignificance according to the testing strategy for overall type-I errorcontrol as indicated.

TABLE 42 Results for Primary Efficacy Endpoints from SensitivityAnalyses PBO UPA 45 mg Adj. Diff Endpoint; n (%) (N = 171) (N = 324)[95% CI] p-value Clinical 24 (14.0) 129 (39.8) 25.9 [18.6, 33.3] <.0001remission per PROs at Week 12 Clinical 34 (19.9) 122 (37.6) 18.0 [10.2,25.8] <.0001 remission per CDAI at Week 12 Per regulatory feedback,sensitivity analyses were conducted using a total of 7-day collectionperiod (i.e., 9 days prior to the visit, excluding the 2 days before andthe day of endoscopy), instead of the originally planned 14-daycollection period, for the PRO and CDAI calculation.

TABLE 43 Results for Selected Key Efficacy Endpoints at the End of EachStudy Part (NRI-C) Part 3 Part 1 Part 2 Week 24 Week 12 Week 12 DB PBO/DB UPA 45/ OL UPA 45/ DB PBO DB UPA 45 OL UPA 45 UPA 45 UPA 30 UPA 30Endpoint; n (%) (N = 171) (N = 324) (N = 129) (N = 78) (N = 69) (N = 14)Clinical remission per 24 (14.0) 129 (39.8) 65 (50.4) 34 (43.6) 16(23.2) 1 (7.1)  PROs¹ Clinical remission per 36 (21.1) 126 (38.9) 68(52.7) 27 (34.6) 17 (24.6) 5 (35.7) CDAI² Endoscopic response³ 6 (3.5)112 (34.6) 46 (35.7) 27 (34.6)  8 (11.6) 3 (21.4) Clinical response⁴ 66(38.6) 211 (65.1) 104 (80.6)  54 (69.2) 34 (49.3) 6 (42.9) Note: Resultsare summarized among the ITT population for each study part, defined assubjects who received at least one dose of study drug in thecorresponding study part. DB: Double blind. OL: Open label. PBO:Placebo. UPA: Upadacitinib. NRI-C: Non-Responder Imputation (NRI)incorporating Multiple Imputation (MI) for missing data due to COVID-19.¹Result at Week 12 in Part 1 is one of the co-primary endpoints forEU/EMA regulatory purposes, as defined herein. ²Result at Week 12 inPart 1 is one of the co-primary endpoints for US/FDA regulatorypurposes, as defined herein. ³Result at Week 12 in Part 1 is one of theco-primary endpoints for both EU/EMA and US/FDA regulatory purposes, asdefined herein. ⁴Subjects who achieved the clinical response were toroll-over to the Maintenance Study M14-430. The clinical response isdefined as the achievement of ≥30% decrease in average daily very softor liquid stool frequency (SF) and/or ≥30% decrease in average dailyabdominal pain (AP) score at Week 12, with both SF and AP not worse thanBaseline.

Example 22: Upadacitinib 15 mg or 30 mg as Maintenance Therapy forCrohn's Disease

This study (Study M14-430) was a Phase 3, multicenter, randomized,double-blind, placebo-controlled maintenance and long-term extensionstudy of the efficacy and safety of upadacitinib (ABT-494) in aubjectswith moderately to severely active Crohn's Disease who completed thestudies M14-431 or M14-433.

Methodology:

Study M14-430 was a Phase 3, multicenter study to evaluate the efficacyand safety of maintenance and long-term treatment administration ofupadacitinib, an orally administered Janus kinase 1 inhibitor, in adultsubjects with CD. Subjects who consented and met all of the inclusioncriteria and none of the exclusion criteria in each substudy wereenrolled. Baseline was defined as the Baseline Visit of Study M14-431 orStudy M14-433 (parent study) and Week 0 was defined as the first studyvisit in Substudy 1 or Substudy 2.

Objectives:

Study M14-430 comprised two substudies.

-   -   Substudy 1 (randomized, double-blind, placebo-controlled        maintenance): To evaluate the efficacy and safety of two doses        of upadacitinib versus placebo as maintenance therapy in        subjects with moderately to severely active Crohn's disease (CD)        who responded to upadacitinib induction treatment in Studies M14        431 or M14-433. Sub-study 1 included a 52-week Maintenance        Period.    -   A schematic of the study design for Substudy 1 is shown in FIG.        52.

Substudy 2 (long term extension [LTE]): To evaluate safety and efficacyof long-term administration of upadacitinib in subjects with moderatelyto severely active CD who participated in the Phase 3 upadacitinibinduction and maintenance studies. Sub-study 2 included a 240-week LTEPeriod. A schematic of the study design for Substudy 2 is shown in FIG.53.

Study Population:

Substudy 1 enrolled subjects who had achieved clinical response (definedas ≥30% decrease in average daily very soft/liquid stool frequency [SF]and/or ≥30% decrease in average daily abdominal pain [AP] score and bothnot worse than Baseline) at Week 12 of the induction Study M14-431 orStudy M14 433 or after the blinded Extended Treatment Period of StudyM14-431 or Study M14-433 at Week 24.

Substudy 2 enrolled subjects who completed Substudy 1 and subjects fromStudy M14-431 (Part 3/Cohort 3) who received open-label upadacitinib 30mg once daily (QD) in the Extended Treatment Period and achievedclinical response at Week 24.

Number of Subjects Enrolled: Approximately 747 subjects, with thefollowing allocation:

-   -   Substudy 1: Approximately 717 subjects from Studies M14-431 and        M14-433    -   Substudy 2: Approximately 30 subjects from Study M14-431 and        approximately 573 subjects (80% of subjects in Substudy 1) who        completed Week 52 of Substudy 1.

Substudy 1 (52-Week, Randomized, Double-Blind, Maintenance)

All subjects who achieved clinical response after 12 weeks of inductiontreatment with upadacitinib or placebo or after blinded treatment in theExtended Treatment Period at Week 24 in Studies M14-431 or M14-433 wereeligible to enroll in Substudy 1, and were blinded to treatmentassignment. Substudy 1 had three cohorts:

Cohort 1:

Approximately 427 subjects who received upadacitinib 45 mg QD inductiontreatment for 12 weeks in Study M14-431 (from Part 1 or Part 2) or StudyM14-433 (Part 1), and approximately 110 subjects who receivedupadacitinib 45 mg QD induction treatment for 12 weeks during theExtended Treatment Period of Study M14-431 (Cohort 1 of Part 3) or StudyM14-433 (Cohort 1 of Part 2) and achieve clinical response werere-randomized in a 1:1:1 ratio to one of the following three treatmentgroups:

-   -   Group 1: upadacitinib 15 mg QD    -   Group 2: upadacitinib 30 mg QD    -   Group 3: placebo

The randomization was stratified by prior induction population (1) StudyM14-433 non-bio-IR, 2) Study M14-433 bio IR or Study M14-431 Part 1/Part3, or 3) Study M14-431 Part 2), clinical remission (per PROs) status(yes or no), and endoscopic response status (yes or no; based on thelocal read) at Week 12 or 24 of Study M14-431 or Study M14-433. The datacollected from approximately 501 subjects re-randomized into this cohortwas used for the primary efficacy analysis.

Cohort 2:

Approximately 120 subjects who received double-blind placebo for 12weeks during Part 1 of Studies M14-431 or M14-433 and achieved clinicalresponse were assigned by interactive response technology (IRT) tocontinue to receive blinded placebo.

Cohort 3:

Approximately 60 subjects who entered the Extended Treatment Period ofStudies M14-431 or M14-433 to receive double blind upadacitinib 30 mg QDfor 12 weeks and achieved clinical response at Week 24 were assigned byIRT to continue to receive blinded upadacitinib 30 mg QD. The finalvisit of Study M14-431 or Study M14-433 (Week 12 or Week 24) was theenrollment visit into Substudy 1. The day of enrollment of Study M14-430was considered the Week 0 visit of Substudy 1. Subjects completed allthe study activities at Week 12 or Week 24 in Study M14 431 or Study M14433, including the endoscopy, and this information was carried over tothe Week 0 visit and served as the reference for all subsequent visits.The duration of Substudy 1 was up to 56 weeks, including a 52-weekmaintenance period and a 30-day follow-up visit (except for subjects whocontinued in Substudy 2) from last dose of study drug. The last dose ofstudy drug during this period was taken the day prior to the Week 52visit. Visits occured at Week 0, 4, 12, 22, 32, 42 and 52/PrematureDiscontinuation (PD). All subjects who completed Week 52 visit inSubstudy 1 (all cohorts) were eligible to enroll into Substudy 2 (LTE).

Substudy 2 (240-Week LTE)

Substudy 2 enrolled subjects from two sources that were managed as twoseparate cohorts.

Cohort 4:

Approximately 30 subjects who achieved clinical response in theopen-label Extended Treatment Period (Part 3/Cohort 3 of Study M14-431)at Week 24 continued to receive open-label upadacitinib 30 mg QD for 240weeks.

Cohort 5:

All subjects who completed Substudy 1 were eligible to enroll in thiscohort. At Week 0, all subjects continued to receive their originallyassigned double-blind treatment (placebo, 15 or 30 mg QD upadacitinib).The treatment assignments were unblinded when the last subject inSubstudy 1 completed Week 52, and all subjects receiving upadacitinibcontinued to receive their treatments until the end of the study. Thesubjects receiving placebo only received the concomitant CD-relatedmedications, if any. Visits occured at Week 0, 4, 12, and every 12 weeksthereafter until Week 240/PD. The final visit of Study M14 431 (Week 24)or Substudy 1 (Week 52) was the enrollment visit into Substudy 2. Thelast dose of study drug during this period was taken the day prior tothe Week 240 visit. The duration of Substudy 2 was up to 244 weeks,including a 240-week period and a 30-day follow up visit from last doseof study drug.

For Substudy 1 and 2, subjects used the same subject electronic diarythat was dispensed for Study M14-431 or Study M14-433, where theycontinued to record CD-related symptoms, use of antidiarrheals, and useof medications for endoscopy preparation throughout the study. Subjectswere re-instructed to record CD-related symptoms and medications. Thediary was reviewed by site personnel with the subject at each visit andfor the assessment of the clinical endpoints; the very soft or liquid SFand AP entries from the most recent 7-day period prior to each studyvisit were used. At each study visit, routine physical examinationincluding evaluation of vital signs, extra-intestinal manifestations,and presence or absence of fistulas; diary review; calculation ofCrohn's Disease Activity Index (CDAI) score, average daily SF, andaverage daily AP score; monitoring of adverse events (AEs); andconcomitant medications was performed. The very soft or liquid SF valuesrepresented the unweighted daily averages of the corresponding subscoresfrom the CDAI. Additionally, subjects completed quality of life (QoL),CD symptoms and symptoms impact on QoL, and work productivityquestionnaires throughout the study.

Subjects underwent a full colonoscopy (ileo-colonoscopy) for evaluationof mucosal inflammation using the Simplified Endoscopic Score forCrohn's disease (SES-CD) at Week 52 (Substudy 1); and at Week 48 andevery 48 weeks thereafter (Substudy 2), and all endoscopies werecentrally read. In Substudy 1, intestinal biopsies during the endoscopicevaluation were collected for histologic exploratory research at Week52/PD in approximately 400 subjects who consented to take part in theintestinal biopsy substudy and had collected biopsies in the inductionStudies M14-431 and M14-433.

Concomitant CD-Related Medications (Antibiotics, Aminosalicylates,and/or Methotrexate)

In Substudy 1, all subjects receiving CD-related antibiotics coulddiscontinue treatment starting at Week 0 at the discretion of theinvestigator. All subjects receiving stable dose of CD-relatedantibiotics (those subjects who did not discontinue), aminosalicylates,or methotrexate (MTX) at Week 0 maintained their concomitant treatmentsand respective doses through the end of the study. Doses of CD-relatedantibiotics, aminosalicylates, or MTX were decreased in the event ofmoderate-to-severe treatment related toxicities. Initiating and/orchanging doses of or starting CD-related antibiotics, aminosalicylates,or MTX was prohibited during the study, with the exception ofdemonstrated inadequate response and need for rescue therapy.

In Substudy 2, doses of CD-related antibiotics, aminosalicylates, or MTXcould be changed at the discretion of the investigator and need to bedocumented in the appropriate electronic case report form.

Concomitant Corticosteroids

In either Substudy 1 or 2, at Week 0, subjects who were taking oralcorticosteroid at Baseline of Study M14 431 or M14-433, and initiatedbut did not completed tapering, continued to have the corticosteroiddose reduced according to a tapering schedule. Initiating locally acting(rectal or suppository) or systemic corticosteroids was prohibitedduring the maintenance treatment period (Substudy 1), with the exceptionof demonstrated inadequate response and need for rescue therapy.

Rescue Treatment

Subjects who demonstrated inadequate response (any cohort) and requiredmedical treatment could receive rescue treatment. The criteria forinadequate response were the following:

-   -   Clinical symptoms: Average daily very soft or liquid SF≥4.0        and/or average daily AP score ≥2.0, AND    -   Objective marker of inflammation:        -   High-sensitivity C-reactive protein (hs-CRP)≥upper limit of            normal, and worse than the lowest value assessed during the            study, or        -   Fecal calprotectin (FCP)≥250 μg/g, and worse than the lowest            value assessed in the present study, or        -   SES-CD, excluding the narrowing component, ≥6 (≥4 for            isolated ileal disease), as scored by the site investigator,            assessed at any scheduled study visit with endoscopy or at            an endoscopy performed at an unscheduled visit at the            investigator's discretion.

Diagnosis and Main Criteria for Inclusion/Exclusion: Main Inclusion:Substudy 1

1. Subject achieved clinical response in Study M14-431 or Study M14-433.2. Subject completed Week 12 (in subjects who achieve response at Week12) or Week 24 (in subjects who achieved response at Week 24) visit andprocedures in Study M14-431 or Study M14-433. Note: Subjects completingPart 3/Cohort 3 of Study M14-431, who received open-label ExtendedTreatment, could enroll in Substudy 2.

Substudy 2

3. Subject completed Week 52 of the maintenance period of Study M14-430(Substudy 1). Completion included the Week 52 endoscopy of Substudy 1.4. Subject achieved clinical response at Week 24 and completed Week 24visit and procedures in Part 3/Cohort 3 of Study M14-431.

Main Exclusion: Substudy 1 and 2

1. Subject was considered by the investigator, for any reason, to be anunsuitable candidate for the study.2. Subject who had a known hypersensitivity to upadacitinib or itsexcipients, or had an AE during Study M14-431, M14-433, or Substudy 1 ofStudy M14-430 that in the investigator's judgment made the subjectunsuitable for this study.3. Subject with any active or chronic recurring infections based on theinvestigator's assessment that made the subject an unsuitable candidatefor the study. Subjects with serious infections undergoing treatmentcould be enrolled BUT NOT dosed until the infection treatment wascompleted, and the infection was resolved, based on the investigator'sassessment.4. Subjects with high grade colonic dysplasia or malignancy diagnosed atthe endoscopy performed at the final visit of Study M14-431, M14-433, orSubstudy 1 of Study M14-430 (Week 52).

Investigational Product: Upadacitinib (ABT-494) Doses: 15 mg QD, 30 mgQD Mode of Administration: Oral Reference Therapy: Placebo Dose: N/AMode of Administration: Oral

Duration of Treatment: Substudy 1 had a duration of 52 weeks andSubstudy 2 had a duration of approximately 240 weeks.

Criteria for Evaluation: Endpoint Definitions

1. Clinical remission per PROs: Average daily soft or liquid SF≤2.8 ANDaverage daily AP score ≤1.0 and both not greater than baseline2. Clinical remission per CDAI: CDAI<1503. Enhanced Clinical Response: ≥60% decrease in average daily very softor liquid SF and/or ≥5% decrease in average daily AP score from Baselineand both not greater than Baseline, or clinical remission per PROs4. Clinical response 100 (CR-100): Decrease of at least 100 points inCDAI from Baseline5. Clinical response: ≥30% decrease in average daily very soft or liquidSF and/or ≥30% decrease in average daily AP score from Baseline and bothnot greater than baseline6. Endoscopic remission: SES-CD≤4 and at least 2-point reduction fromBaseline and no subscore >1 in any individual variable, as scored bycentral reviewer7. Endoscopic response: Decrease in SES-CD>50% from Baseline of theinduction study (or for subjects with an SES-CD of 4 at Baseline of theinduction study, at least a 2-point reduction from Baseline of theinduction study), as scored by central reviewer. Note: Baseline is fromthe induction Study M14-431 or Study M14-433.

Efficacy: Substudy 1, Cohort 1 (Upadacitinib vs Placebo)

The co-primary and ranked secondary endpoints were analyzed separatelyfor EU/EMA and US/FDA regulatory purposes; these endpoints werespecified separately for each set of analyses.

EU/EMA Endpoints Co-Primary Endpoints:

-   -   Proportion of subjects with clinical remission per PROs at Week        52, AND    -   Proportion of subjects with endoscopic response at Week 52

Ranked Secondary Endpoints:

1. Proportion of subjects with clinical remission per CDAI at Week 522. Proportion of subjects with endoscopic remission at Week 52

3. Change in Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ)at Week 52

4. Proportion of subjects achieving CR-100 at Week 525. Proportion of subjects without corticosteroid use for CD at least 90days prior to Week 52 and achieved clinical remission per PROs at Week52 (among all subjects)6. Proportion of subjects who discontinued corticosteroid use for CD atleast 90 days prior to Week 52 and achieved clinical remission per PROsat Week 52 in subjects taking corticosteroids for CD at Baseline ofinduction7. Proportion of subjects with clinical remission per PROs at Week 0 andWeek 528. Change from Baseline in Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) at Week9. Proportion of subjects with clinical remission per PROs andendoscopic remission at Week 5210. Proportion of subjects with CD-related hospitalizations during the52-Week double-blind maintenance period11. Proportion of subjects with resolution of extra-intestinalmanifestations (EIMs) at Week 52, in subjects with EIMs at Baseline.

US/FDA Endpoints Ranked Secondary Endpoints for US/FDA RegulatoryPurposes:

1. Proportion of subjects with clinical remission per PROs at Week 522. Proportion of subjects achieving CR-100 at Week 523. Proportion of subjects with endoscopic remission at Week 524. Proportion of subjects without corticosteroid use for CD at least 90days prior to Week 52 and achieved clinical remission per CDAI at Week52 (among all subjects)5. Proportion of subjects with clinical remission per CDAI andendoscopic remission at Week 526. Proportion of subjects with clinical remission per CDAI at Week 0 andWeek 527. Proportion of subjects who discontinued corticosteroid use for CD atleast 90 days prior to Week 52 and achieved clinical remission per CDAIat Week 52, in subjects taking corticosteroids at Baseline of induction8. Change from Baseline in Inflammatory IBDQ at Week 529. Change from Baseline in FACIT-F at Week 5210. Proportion of subjects with hospitalizations due to CD during the52-week double-blind maintenance period11. Proportion of subjects with resolution of EIMs at Week 52, insubjects with EIMs at Baseline.

Substudy 2 Primary Endpoint: Incidence of AEs Over Time

Additional efficacy endpoints included the following:

Proportion of Subjects

-   -   with clinical remission per PROs over time    -   with enhanced clinical response over time    -   with clinical response over time    -   with clinical remission per CDAI over time    -   with CR-100 over time    -   with endoscopic remission at Week 0, and every 48 weeks        thereafter    -   with endoscopic response at Week 0, and every 48 weeks        thereafter    -   without corticosteroid use for CD and achieve clinical remission        per PROs over time    -   without corticosteroid use for CD and achieve clinical remission        per CDAI over time

Time to Loss of:

-   -   enhanced clinical response    -   clinical remission per PROs    -   clinical remission per CDAI

Pharmacokinetic (Substudy 1 Only):

Blood samples for assay of upadacitinib were collected at specificvisits any time during the visit.

Safety:

Safety analyses were performed on all subjects who receive at least onedose of study drug. Incidence of AEs, changes in vital signs, physicalexamination results, and clinical laboratory data were assessedthroughout the study.

Statistical Methods: Efficacy: Substudy 1 (Cohort 1)

Efficacy analysis was based on the intent-to-treat (ITT1) analysis set,which included the first randomized subjects, approximately 501, who hadtaken at least one dose of study drug in the double blind maintenanceperiod. The comparison between treatment groups on the co-primaryefficacy endpoints was performed using the Cochran-Mantel-Haenszel (CMH)test and stratified by prior induction study population 1) Study M14433, non-bio-IR, 2) Study M14-433 bio-IR, or Study M14-431 Part 1/Part3, 3) Study M14 431 Part 2, clinical remission per PROs (yes or no), andendoscopic response status (per local read) (yes or no) at Week 12 ofStudy M14-431 or Study M14-433, or Week 24 for those subjects whoreceived blinded induction treatment with upadacitinib 45 mg QDinduction treatment for 12 weeks during the Extended Treatment Period ofStudy M14-431 (Cohort 1 of Part 3) or Study M14-433 (Cohort 1 of Part2).

Both of the co-primary efficacy endpoints were tested at two sidedsignificance level of 0.025 for each of the upadacitinib dose groupsversus placebo to adjust for multiplicity. A CMH based two-sided 95%confidence interval for the difference between treatment groups wascalculated. If average daily very soft or liquid SF or AP score (EU/EMA)or CDAI (US/FDA at Week 52 were missing, the non-responder imputation(NRI) approach was applied for the clinical remission per PROs at Week52 and clinical remission per CDAI at Week 52 endpoints, respectively.Subjects who discontinued prior to Week 52 for any reason or whoinitiated rescue therapy were considered as “not achieved” for clinicalremission or endoscopic response endpoints.

Secondary efficacy variables were divided into two groups. The firstgroup included ranked secondary endpoints, which were ranked by clinicalimportance. The second group included all other non-ranked secondaryvariables.

A multiple testing procedure was used to provide strong control of thetype 1 error rate at alpha (α)=0.05 (2-sided) across analyses comparingeach upadacitinib dose group to placebo with respect to the co-primaryendpoints and ranked secondary endpoints. Specifically, testing utilizeda sequence of hypothesis testing for the co-primary endpoints followedby the ranked secondary endpoints, and began with testing each of theco-primary endpoints using α of 0.025 (2-sided) for each dose comparedto placebo. If both co-primary endpoints achieved statisticalsignificance within a dose level, continued testing followed apre-specified weight of a allocation between the single hypothesiswithin the family, as well as between families of hypotheses across thedoses. In general, continuous secondary efficacy variables with repeatedmeasurements were analyzed using a Mixed Effect Repeated Measure (MMRM)model. Continuous secondary efficacy variables which were collected atonly one post-baseline visit (such as SES-CD) were analyzed using anAnalysis of Covariance (ANCOVA) model. Categorical secondary efficacyvariables were analyzed using the CMH test controlling forstratification variables. NRI for missing data was used for categoricalsecondary endpoints.

Substudy 1 (Cohorts 2 and 3) and Substudy 2

All analyses of efficacy endpoints were performed using the ITT analysisset. Descriptive statistics are provided. Categorical data wassummarized by number and percent; and quantitative data was presented byn, mean, standard deviation, minimum value, median, and maximum value.

Pharmacokinetic:

A non-linear mixed-effects modeling approach was used to estimate thepopulation central values and the empirical Bayesian estimates of theindividual values of upadacitinib oral clearance and volume ofdistribution. Additional parameters were estimated if useful in theinterpretation of the data. Data from this study could be combined withdata from other studies for the population pharmacokinetic analyses.

Safety:

All safety comparisons were performed between treatment groups using thesafety analysis set, which consisted of all subjects who received atleast one dose of the study drug in the double-blind maintenance period.Treatment-emergent AEs were defined as events that began or worsenedeither on or after the first dose of the study drug and within 30 daysafter the last dose of the study drug for subjects who do notparticipate in Substudy 2 or within 30 days after the last dose of thestudy drug in Substudy 2. An overview of treatment-emergent AEs,including AEs of special interest, AEs leading to death, AEs leading topremature discontinuation, AEs by Medical Dictionary for Drug RegulatoryActivities preferred term and system organ class, AEs by maximumrelationship to study drug, and AEs by maximum severity were summarizedby number and percentage. Changes from Baseline and from Week 0 inlaboratory data were described using statistical characteristics andcomparison between-treatment groups will be performed using a one-wayanalysis of variance. Vital signs and laboratory data were described bystatistical characteristics and frequency of abnormal values. Inaddition, shift tables and listings are provided for abnormal values,whereby the normal range of the analyzing laboratory was used.

Differences Statement

This study was designed to evaluate the efficacy and safety ofupadacitinib 15 mg QD and 30 mg QD versus placebo as maintenance therapyin subjects with moderately to severely active CD. The primarydifferences between Study M14-430 and the parent studies (StudiesM14-431 and M14-433) were that this study evaluated lower upadacitinibdoses than the 45 mg QD induction dose, and for a long period of time ofat least 52 weeks and up to 240 weeks.

Study Objective

Study M14-430 comprised two substudies:

-   -   The objective of Substudy 1 (randomized, double-blind,        placebo-controlled maintenance) was to evaluate the efficacy and        safety of two doses of upadacitinib versus placebo as        maintenance therapy in subjects with moderately to severely        active CD who responded to upadacitinib induction treatment in        Studies M14-431 or M14-433.    -   The objective of Substudy 2 (long-term extension [LTE]) was to        evaluate safety and efficacy of long-term administration of        upadacitinib in subjects with moderately to severely active CD        who participated in the Phase 3 upadacitinib induction and        maintenance studies.

Overall Study Design and Plan

Study M14-430 was a Phase 3, multicenter study to evaluate the efficacyand safety of maintenance and long-term treatment administration ofupadacitinib, an orally administered JAK1 inhibitor, in adult subjectswith CD. The study was designed to enroll approximately 747 subjects atapproximately 400 study centers worldwide to meet scientific andregulatory objectives without enrolling an undue number of subjects inalignment with ethical considerations. The two substudies (Substudy 1and Substudy 2; FIGS. 52 and 53, respectively) enrolled concurrently.Baseline was defined as the Baseline Visit of Study M14-431 or StudyM14-433 (parent study) and Week 0 was defined as the first study visitin Substudy 1 or Substudy 2.

Substudy 1 (52-Week, Randomized, Double-Blind, Maintenance)

All subjects who achieved clinical response after 12 weeks of inductiontreatment with upadacitinib or placebo or after blinded treatment in theExtended Treatment Period at Week 24 in Studies M14-431 or M14-433 wereeligible to enroll in Substudy 1, and were blinded to treatmentassignment. Substudy 1 had three cohorts:

Cohort 1: Approximately 427 subjects who received upadacitinib 45 mg QDinduction treatment for 12 weeks in Study M14-431 (from Part 1 or Part2) or Study M14-433 (Part 1), and approximately 110 subjects whoreceived upadacitinib 45 mg QD induction treatment for 12 weeks duringthe Extended Treatment Period of Study M14-431 (Cohort 1 of Part 3) orStudy M14-433 (Cohort 1 of Part 2) and achieve clinical response werere-randomized in a 1:1:1 ratio to one of the following three treatmentgroups:

-   -   Group 1: upadacitinib 15 mg QD    -   Group 2: upadacitinib 30 mg QD    -   Group 3: placebo

The randomization was stratified by prior induction population (1) StudyM14-433 non-bio-IR, 2) Study M14-433 bio-IR or Study M14-431 Part 1/Part3, 3) Study M14-431 Part 2, clinical remission (per PROs) status (yes orno), and endoscopic response status (yes or no; based on the local read)at Week 12 or 24 of Study M14-431 or Study M14-433. It was expected thatapproximately 501 subjects would be re-randomized into Cohort 1 ensuringat least 90% power for simultaneous achievement for the co primaryendpoints of clinical remission (per PROs for EU/EMA regulatory purposesand per CDAI for US/FDA regulatory purposes) at Week 52 and endoscopicresponse at Week 52. The data collected from approximately 501 subjectsre-randomized into this cohort was used for the primary efficacyanalysis. For this stratification, the endoscopic score of Study M14-431or Study M14-433 at Baseline from central reader and the endoscopicscore at Week 12 or 24 from site local reader was used in order todetermine endoscopic response status. The central reader endoscopicscore was used for calculating the endoscopic response for theevaluation of the efficacy endpoints.

Cohort 2: Approximately 120 subjects who received double-blind placebofor 12 weeks during Part 1 of Study M14-431 or Study M14-433 andachieved clinical response were assigned by interactive responsetechnology (IRT) to continue to receive blinded placebo.

Cohort 3: Approximately 60 subjects who entered the Extended TreatmentPeriod of Study M14-431 or M14-433 to receive double-blind upadacitinib30 mg QD for 12 weeks and achieved clinical response at Week 24 wereassigned by IRT to continue to receive blinded upadacitinib 30 mg QD.

The last dose of study drug during this period was taken the day priorto the Week 52 visit. The final visit of Study M14-431 or Study M14-433(Week 12 or Week 24) was the enrollment visit into Substudy 1. Subjectscompleted all the study activities at Week 12 or Week 24 in StudyM14-431 or Study M14-433, including the endoscopy, and this informationwas carried over to the Week 0 visit and served as the reference for allsubsequent visits. The duration of Substudy 1 was up to 56 weeks,including a 52-week maintenance period and a 30-day follow-up visit(except for subjects who continue in Substudy 2) from last dose of studydrug. Visits will occur at Week 0, 4, 12, 22, 32, 42 and 52/PrematureDiscontinuation (PD).

A ±7-day window was permitted around scheduled study visits. At or afterWeek 4, subjects who met the criteria for inadequate response andrequired medical treatment (including subjects who met these criteriaprior to protocol Amendment 4) could receive rescue therapy. Allsubjects who completed Week 52 visit in Substudy 1 (all cohorts) wereeligible to enroll into Substudy 2 (LTE). Subjects who completed Week 52were not eligible to enter Substudy 2 until the ileo-colonoscopy at Week52 had been completed.

Subjects who prematurely discontinued from the study or who did notcontinue into Substudy 2 had an additional 30-day follow-up visit fromthe last dose of study drug to collect information about new or ongoingAEs and laboratory assessments. Subjects were discontinued from thestudy if they withdrew consent or if they were deemed unsuitable tocontinue for any reason by the investigator.

Substudy 2 (240-Week Long-Term Extension)

Substudy 2 enrolled subjects from two sources that were managed as twoseparate cohorts.

Cohort 4: Approximately 30 subjects who achieved clinical response inthe open-label Extended Treatment Period (Part 3/Cohort 3 of StudyM14-431) at Week 24 continued to receive open-label upadacitinib 30 mgQD for 240 weeks. At or after Week 4, subjects who met the criteria forinadequate response and required medical treatment could receive rescuetreatment.

Cohort 5: All subjects who completed Substudy 1 were eligible to enrollin this cohort. At Week 0, all subjects continued to receive theiroriginally assigned double-blind treatment (placebo, 15 or 30 mg QDupadacitinib). The treatment assignments were unblinded when the lastsubject in Substudy 1 completed Week 52, and all subjects receivingupadacitinib continued to receive their treatments until the end of thestudy. The subjects receiving placebo only received the concomitantCD-related medications, if any. During Substudy 2, subjects who met thecriteria for inadequate response could receive rescue treatment.

Visits occurred at Week 0, 4, 12, and every 12 weeks thereafter untilWeek 240/PD. The final visit of Study M14-431 (Week 24) was theenrollment visit of Substudy 2. The day of enrollment of Substudy 2M14-430 was considered the Week 0 visit of Substudy 2. A ±7-day windowwas permitted around scheduled study visits. The last dose of study drugduring this period was taken the day prior to the Week 240 visit. Theduration of Substudy 2 was up to 244 weeks, including a 240-week periodand a 30-day follow-up visit from last dose of study drug. All subjectscompleted all study activities, including the endoscopy during StudyM14-431 or Substudy 1 before entering into Substudy 2, and thisinformation was carried over to the Week 0 visit and served as thereference for all subsequent visits and assessments. Subjects whoprematurely discontinued from the study had a 30-day follow-up visitfrom the last dose of study drug to collect information about new orongoing AEs and laboratory assessments.

For Substudy 1 and 2, subjects used the same subject electronic diarythat was dispensed for Study M14-431 or Study M14-433, where theycontinued to record CD-related symptoms, use of antidiarrheals, and useof medications for endoscopy preparation throughout the study. Subjectswere re-instructed to record CD-related symptoms and medications. Thediary was reviewed by site personnel with the subject at each visit andfor the assessment of the clinical endpoints; the stool frequency (SF)and abdominal pain (AP) entries from the most recent 7-day period priorto each study visit was used.

At each study visit, routine physical examination including evaluationof vital signs, extra-intestinal manifestation (EIMs), presence orabsence of fistulas; diary review; calculation of Crohn's DiseaseActivity Index (CDAI) score, average daily very soft or liquid SF, andaverage daily AP score; monitoring of AEs; and concomitant medicationswas performed. The very soft or liquid SF values represented theunweighted daily averages of the corresponding subscores from the CDAI.Additionally, subjects complete dQoL, CD symptoms and symptoms impact onQoL, and work productivity questionnaires throughout the study.

Clinical samples for urinalysis, chemistry and hematology,high-sensitivity C-reactive protein (hs-CRP) were collected. Plasmaupadacitinib concentrations was assessed in Substudy 1 only. Inaddition, stool samples for calprotectin analysis were collected andtaken before starting bowel preparations for endoscopy. Subjectsunderwent a full colonoscopy (ileo-colonoscopy) for evaluation ofmucosal inflammation using the Simplified Endoscopic Score for Crohn'sdisease (SES-CD) at Week 52 (Substudy 1); and at Week 48 and every 48weeks thereafter (Substudy 2), and all endoscopies were centrally read.In Substudy 1, intestinal biopsies during the endoscopic evaluation werecollected for histologic exploratory research at Week 52/PD inapproximately 400 subjects who consented to take part in the intestinalbiopsy substudy and had collected biopsies in the induction StudiesM14-431 and M14-433.

Selection of Study Population

It was anticipated that approximately 747 subjects (approximately 717subjects in Substudy 1 and approximately 30 subjects in Substudy 2) withCD would be enrolled at approximately 400 sites worldwide. A subjectcould be enrolled in this study provided that he/she met all of theinclusion criteria and none of the exclusion criteria of this protocol.Substudy 1 enrolled subjects who achieved clinical response (defined as≥30% decrease in average daily very soft or liquid SF and/or ≥30%decrease in average daily AP score and both not worse than Baseline) atWeek 12 of the induction Study M14-431 or Study M14-433 or after theblinded Extended Treatment Period of Study M14-431 or Study M14-433 atWeek 24. Substudy 2 enrolled subjects who completed Substudy 1 andsubjects from Study M14-431 (Part 3/Cohort 3) who received open-labelupadacitinib 30 mg QD in the Extended Treatment Period and achievedclinical response at Week 24.

Substudy 1

1. Subject achieved clinical response in Study M14-431 or Study M14-433.2. Subject completed Week 12 (in subjects who achieved response at Week12) or Week 24 (in subjects who achieve response at Week 24) visit andprocedures in Study M14-431 or Study M14-433. Note: Subjects completingPart 3/Cohort 3 of Study M14-431, who received open-label ExtendedTreatment, enrolled in Substudy 2.

Substudy 2

3. Subject completed Week 52 of the maintenance period of Study M14-430(Substudy 1). Completion included the Week 52 endoscopy of Substudy 1.4. Subject achieved clinical response at Week 24 and completed Week 24visit and procedures in Part 3/Cohort 3 of Study M14-431.

Exclusion Criteria Substudy 1 and 2

1. Subject considered by the investigator, for any reason, to be anunsuitable candidate for the study.2. Subject who had a known hypersensitivity to upadacitinib or itsexcipients, or had an AE during Studies M14-431, M14-433, or Substudy 1of Study M14-430 that, in the investigator's judgment, made the subjectunsuitable for this study.3. Subjects who anticipated the need for any live vaccine during studyparticipation including at least 30 days (or longer, if required locally[e.g., 8 weeks for Japan]) after the last dose of study drug.4. Female subjects with a confirmed positive pregnancy test at the finalvisit in Studies M14-431, M14-433, or Substudy 1 of Study M14-430, orwho were considering becoming pregnant during the study.5. Subject was not in compliance with prior and concomitant medicationrequirements throughout Studies M14-431, M14-433, or Substudy 1 of StudyM14-430.6. Subject with any active or chronic recurring infections based on theinvestigator's assessment made the subject an unsuitable candidate forthe study. Subjects with serious infections undergoing treatment couldbe enrolled BUT NOT dosed until the infection treatment had beencompleted, and the infection was resolved, based on the investigator'sassessment.7. Evidence of active or untreated latent tuberculosis8. Subjects with high grade colonic dysplasia or malignancy diagnosed atthe endoscopy performed at the final visit of Studies M14-431, M14-433,or Substudy 1 of Study M14-430 (Week 52).9. Current or history of malignancy or lymphoproliferative disease,including lymphoma, or signs and symptoms suggestive of possiblelymphoproliferative disease, such as lymphadenopathy and/orsplenomegaly; except for successfully treated non-metastatic cutaneoussquamous cell, basal cell carcinoma, and/or localized carcinoma in situof the cervix.10. Subject with a poorly controlled medical condition, such asuncontrolled diabetes, unstable ischemic heart disease, moderate orsevere congestive heart failure, recent cerebrovascular accidents, andany other condition which, in the opinion of the investigator orsponsor, put the subject at risk by participation in this study.11. Laboratory values from the visit immediately prior to the Week 0Visit meeting the following criteria:

-   -   AST or ALT>3×upper limit of normal (ULN)    -   Total WBC count <2,000/μL,    -   Absolute neutrophil count (ANC)<1,000/μL    -   Platelet count <50,000/μL    -   Absolute lymphocyte count <500/μL    -   Hemoglobin <8 g/dL        12. Enrollment in another interventional clinical study while        participating in this study.

Prior Therapy

Any medication or vaccine (including over-the-counter or prescriptionmedicines, vitamins and/or herbal supplements) that was ongoing at theend of Study M14-431 or Study M14-433 and/or that the subject receivedduring the study, was recorded along with the reason for use, date(s) ofadministration including start and end dates, and dosage informationincluding dose, route and frequency on the appropriate electronic casereport form (eCRF).

Concomitant Therapy

Changes in all concomitant medications were assessed at each study visitfrom Week 0 through Week 52/PD in Substudy 1 and from Week 0 throughWeek 240/PD in Substudy 2. Any changes were documented in the sourcedocuments and captured on the appropriate eCRF page.

Concomitant Crohn's Disease-Related Medications (Antibiotics,Aminosalicylates, and/or Methotrexate)

Substudy 1

All subjects receiving CD-related antibiotics could discontinuetreatment starting at Week 0 at the discretion of the investigator. Allsubjects receiving stable dose of CD-related antibiotics (those subjectswho did not discontinue), aminosalicylates, or MTX at Week 0 maintainedtheir concomitant treatments and respective doses through the end of thestudy. Doses of CD-related antibiotics, aminosalicylates, or MTX couldbe decreased in the event of moderate-to-severe treatment relatedtoxicities. Initiating and/or changing doses of CD-related antibiotics,aminosalicylates, or MTX wais prohibited during the study, with theexception of demonstrated inadequate response and need for rescuetherapy.

Substudy 2

In Substudy 2, doses of CD-related antibiotics, aminosalicylates, or MTXcould be changed at the discretion of the investigator and were bedocumented in the appropriate eCRF. Setons were authorized asconcomitant therapy in subjects with perianal fistulas and documented inthe eCRF under concomitant medications.

Concomitant Corticosteroids

At Week 0 in either Substudy 1 or 2, subjects who were taking oralcorticosteroid at Baseline of Study M14-431 or Study M14-433, andinitiated but had not completed tapering, continued to have thecorticosteroid dose reduced according to the tapering schedule describedherein. Initiating locally acting (rectal or suppository) or systemiccorticosteroids was prohibited during the maintenance treatment period(Substudy 1), with the exception of demonstrated inadequate response andneed for rescue therapy. Use of inhaled or topical (except rectal orsuppository) corticosteroids was not restricted. Subjects could not beon both budesonide (for CD disease) and prednisone (or equivalent)simultaneously.

Prohibited Therapy Biologic Therapies

Therapies including but not limited to the following biologic therapieswere prohibited medications during the study: Adalimumab, Etanercept,Infliximab, Abatacept, Anakinra, Rituximab, Natalizumab, Tocilizumab,Golimumab, Certolizumab, Ustekinumab, Belimumab, Secukinumab,Vedolizumab.

Strong CYP3A Inhibitors or Inducers

Systemic use of known strong cytochrome P450 (CYP) 3A inhibitors orstrong CYP3A inducers was excluded from the Screening Visit through theend of the study. The most common strong CYP3A inhibitors include:Boceprevir, Cobicistat, Clarithromycin, Conivaptan, Grapefruit (fruit orjuice), Indinavir, Itraconazole, Ketoconazole, Lopinavir/Ritonavir,Mibefradil, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Saquinavir,Telaprevir, Telithromycin, Troleandomycin, and Voriconazole. The mostcommon strong CYP3A inducers include: Avasimibe, Carbamazepine,Phenytoin, Rifampin (rifampicin), Rifapentine, and St. John's Wort.

Vaccines

Although not mandated by the protocol, vaccines recommended by localguidelines were considered, except for live vaccines, which were NOTallowed during the study or 30 days (longer, if required locally) afterthe last dose of oral study drug. Examples of live vaccines include, butare not limited to, the following:

-   -   Monovalent live influenza A (H1N1) (intranasal)    -   Seasonal trivalent live influenza (intranasal)    -   Zostavax (herpes zoster, live attenuated)    -   Rotavirus    -   Varicella (chicken pox)    -   Measles-mumps-rubella or measles mumps rubella varicella    -   Oral polio vaccine    -   Smallpox    -   Yellow fever    -   Bacille Calmette-Guérin (BCG)    -   Typhoid (oral)

Examples of common vaccines that are inactivated, toxoid orbiosynthetic, include but are not limited to: injectable influenzavaccine, pneumococcal, herpes zoster (Shingrix non-live, recombinant),and pertussis (tetanus-diphtheria-acellular pertussis) vaccines.

Other Medications Prohibited During the Study:

-   -   JAK inhibitors (e.g., tofacitinib [Xeljanz®])    -   Cyclosporine, tacrolimus, thalidomide, mycophenolate mofetil,        AZA, or 6-MP    -   Nonsteroidal anti-inflammatory drugs (NSAIDs) (except topical        NSAIDs and the use of low dose aspirin for cardiovascular        protection)    -   Rectal therapy with any therapeutic enemas or suppositories,        with the exception of those required for endoscopy    -   Any parenteral nutrition and exclusive enteral nutrition    -   Oral or parenteral Traditional Chinese Medicine    -   Investigational drugs    -   Cytapheresis treatment (granulocytapheresis, etc.) (in Japan and        China only)    -   Cannabis

Rescue Therapy

Subjects who demonstrated inadequate response (any cohort) and requiredmedical treatment could receive rescue treatment. These subjects wereconsidered non-responders for the efficacy endpoints from this pointforward, but could continue in the study for the safety assessments. Thecriteria for inadequate response were:

-   -   Clinical symptoms: Average daily very soft or liquid SF≥4.0        and/or average daily AP score ≥2.0, AND    -   Objective marker of inflammation:        -   hs-CRP≥ULN, and worse than the lowest value assessed during            the study or    -   Fecal calprotectin (FCP)≥250 μg/g, and worse than the lowest        value assessed in the present study, or    -   SES-CD, excluding the narrowing component, ≥6 (≥4 for isolated        ileal disease), as scored by the site investigator, assessed at        any scheduled study visit with endoscopy or at an endoscopy        performed at an unscheduled visit at the investigator's        discretion.

Note: At all visits (except Week 4), if the results of hs-CRP and/orfecal calprotectin were unavailable, the results of these from the priorvisit could be used for the assessment of inadequate response. In casesin which the endoscopy (scheduled or unscheduled) was being used foreligibility for rescue therapy, the local scoring was used to confirmcriteria for inadequate response. The SES-CD from the endoscopy at Week12 or Week 24 of the induction Studies M14-431 and M14-433 could not beused for determination of criteria for inadequate response. Assessmentof inadequate response included consideration by the investigator torule out symptoms caused by reasons other than CD-related inflammation.At or after Week 4 of Substudy 1 (all cohorts) and during Substudy 2Cohort 5, subjects who met the criteria for inadequate response andrequired medical treatment (including those who met the criteria priorto amendment 4), could receive rescue therapy with open labelupadacitinib 30 mg QD from that point forward and until the end of thefollow up. At or after 4 weeks receiving open-label upadacitinib 30 mgQD (including subjects in Cohort 4), subjects who met the criteria forinadequate response and required medical treatment could initiate orincrease the dose, at the investigator's discretion, of any CD-relatedmedication to treat new or worsening of CD symptoms. The allowedCD-related medications were locally acting, oral, or intravenouscorticosteroids, aminosalicylates, MTX, or CD-related antibiotics.Antidiarrheal for control of chronic diarrhea was not considered rescuetreatment. AZA, 6-MP, cyclosporine, and tacrolimus were prohibitedmedications during the study and could not be used as a rescuetreatment. Changes in CD-related concomitant medications were documentedin the appropriated eCRF. After an additional 4 weeks, at theinvestigator's discretion, subjects could adjust (initiate or increase)the dose of any CD-related medication described above. If the subjectcontinued to meet the criteria for inadequate response after theadjustment of rescue therapy with the allowed CD-related medications atthe next study visit, the subject was discontinued from the study.Rescue treatment with allowed CD-related medications was not be withheldeven if subject did not meet the criteria for “inadequate response” ifin the opinion of the investigator, failure to prescribe them would havecompromise the subject's safety. Subjects could also be discontinued atany time based on the investigator's medical assessment. For subjectsreceiving corticosteroids as a rescue treatment, the investigator wasencouraged to initiate tapering based on the subject clinical responsestatus.

Clinical Laboratory Tests

Samples were obtained for the clinical laboratory tests listed in Table44 and at specified visits. Unscheduled clinical labs could be obtainedat any time during the study if deemed appropriate per investigator'sdiscretion. A certified central laboratory was utilized to process andprovided results for the clinical laboratory tests. A laboratory testvalue that required a subject to be discontinued from study drug orrequired a subject to receive treatment was recorded as an AE. Otherlaboratory abnormalities, including those which met the toxicitymanagement criteria outlined herein, were recorded as AEs at thediscretion of the investigator.

TABLE 44 Clinical Laboratory Tests Other Laboratory Hematology ClinicalChemistry^(a) Urinalysis Tests Hematocrit BUN Specific gravity Serumpregnancy (bHCG) testb Hemoglobin Creatinine Ketones QuantiFERON-TBGoldc RBC Count Total Bilirubin pH hs-CRP WBC Count ALT Protein FSHdNeutrophils AST Blood INR (reflex only)e Bands Alkaline PhosphataseGlucose Lymphocyte Subsetsf Lymphocytes CPK Urobilinogen PK MonocytesNa, K, Ca Bilirubin Urine pregnancy testg Basophils Cl LeukocytesEosinophils Bicarbonate Nitrites Reticulocyte count Inorganic phosphateMicroscopic examination, if needed Platelet count Uric acid CholesterolStool Samples LDL/HDL Fecal calprotectin (FCP) Triglycerides Totalprotein Albumin Glucose ALT = alanine transaminase; AST = aspartatetransaminase; bHCG = beta human chorionic gonadotropin; BUN = blood ureanitrogen; CPK = creatine phosphokinase; FSH = follicle-stimulatinghormone; HDL-C = high-density lipoprotein cholesterol; hs-CRP =high-sensitivity C-reactive protein; INR = international normalizedratio; LDL-C = low-density lipoprotein cholesterol; RBC = red bloodcell; TB = tuberculosis; WBC = white blood cell; INR was only bemeasured if ALT and/or AST >3 × ULN; Lymphocyte subsets include T(cluster of differentiation [CD4]+ and CD8+) cells, B (CD19+) cells, NKcells, and natural killer-T cells.

Other Laboratory Assessments

High-Sensitivity C-Reactive Protein (hs-CRP)

Blood samples for hs-CRP were obtained as specified. For both Substudy 1and 2, at or after Week 4, the hs-CRP results were blinded to thesponsor, investigator, study site personnel and the subject. The hs-CRPtest was performed by the central lab.

Urinalysis

Dipstick urinalysis (macroscopic analysis) was completed by the centrallaboratory at all required visits. A microscopic urinalysis was onlyperformed by the central laboratory if the dipstick urinalysis resultswere abnormal, where abnormal was defined as leukocytes, nitrite,ketone, protein, blood, or glucose value of greater than a trace.

Lymphocyte Subsets

Blood samples were collected at specified visits during Substudy 1 onlyto assess lymphocyte subsets: T (cluster of differentiation [CD]4+ andCD8+) cells, B (CD19+) cells, NK cells, and NKT cells.

Outcomes and Questionnaires

The following outcomes and questionnaires were completed at theappropriate time points:

-   -   Inflammatory Bowel Disease Questionnaire (IBDQ)    -   Work Productivity and Activity Impairment Questionnaire        (WPAI)-CD    -   Crohn's Symptoms Severity (CSS) Questionnaire    -   Short Form-36 (SF-36)    -   European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)    -   Functional Assessment of Chronic Illness Therapy-Fatigue        (FACIT-F)    -   Patient Global Impression of Change (PGIC)    -   Patient Global Impression of Severity (PGI-S)    -   Bristol Stool Chart

Study Drug Dispensing/Administration

Study drug was dispensed to subjects at Week 0 and at each visit throughWeek 228, with the exception of Week 4. Study drug was to be takenorally QD beginning at Week 0 and to be taken at approximately the sametime each day.

Crohn's Disease Activity Index (CDAI)

Average daily very soft or liquid SF, average daily AP score, andwell-being were calculated from the subject diary. During Week 0subjects were re-instructed on how to calculate the number of very softand liquid stools, including a visual depiction based on the BristolStool Chart. Physical exam and appropriate laboratory values werecalculated at all study visits, except the 30-day follow-up visit. TheCDAI scores were calculated using a hematocrit (Hct) value from the samevisit laboratory work. The final CDAI for each visit was calculated oncethe Hct value was received from the central lab.

Endoscopy

An endoscopy (ileocolonoscopy) will be performed. For subjects inSubstudy 1, it is expected that all subjects who remain in the studythrough at least Week 8 will have a Week 52/PD endoscopy.

Corticosteroid Taper

At Week 0, subjects who were taking corticosteroid at Baseline of StudyM14-431 or Study M14-433, have initiated but had not completed tapering,continued to have the corticosteroid dose reduced according to atapering schedule. If a subject was unable to tolerate thecorticosteroid taper, the subject could have the taper stopped or theircorticosteroid dose increased, per the investigator's discretion, up tothe dose used at Baseline of Study M14-431 or Study M14-433. If thesubject experienced loss of adequate response during or after thecorticosteroid taper and fulfilled the criteria for inadequate responseand needed medical treatment, the rescue treatment may have beenapplied. With the exception of rescue therapy due to demonstratedinadequate response, initiating locally acting (rectal or suppository)or systemic corticosteroids was prohibited during the maintenancetreatment period (Substudy 1), and was considered a protocol deviation.

Efficacy Variables

The following endpoint definitions apply to the efficacy variablesdescribed below:

-   -   Clinical remission per PROs: Average daily very soft or liquid        SF≤2.8 AND average daily AP score ≤1.0 and both not greater than        Baseline    -   Clinical remission per CDAI: CDAI<150    -   Enhanced Clinical Response: ≥60% decrease in average daily very        soft or liquid SF and/or ≥35% decrease in average daily AP score        from Baseline and both not greater than Baseline, or clinical        remission per PROs    -   Clinical response 100 (CR-100): Decrease of at least 100 points        in CDAI from Baseline    -   Clinical response: ≥30% decrease in average daily very soft or        liquid SF and/or ≥30% decrease in average daily AP score and        both not greater than Baseline    -   Endoscopic remission: SES-CD≤4 and at least 2-point reduction        from Baseline and no subscore >1 in any individual variable, as        scored by central reviewer    -   Endoscopic response: Decrease in SES-CD>50% from Baseline of the        induction study (or for subjects with an SES-CD of 4 at Baseline        of the induction study, at least a 2-point reduction from        Baseline of the induction study), as scored by central reviewer        Note: Baseline is from induction Study M14-431 or Study M14-433.

Substudy 1 Efficacy Variables

The primary analyses were conducted separately for EU/EMA and US/FDAregulatory purposes; the primary endpoint was specified separately foreach set of analyses.

Co-primary endpoints for EU/EMA regulatory purposes:

-   -   Proportion of subjects with clinical remission per PROs at Week        52, AND    -   Proportion of subjects with endoscopic response at Week 52        Co-primary endpoints for US/FDA regulatory purposes:    -   Proportion of subjects with clinical remission per CDAI at Week        52, and    -   Proportion of subjects with endoscopic response at Week 52.

The ranked secondary endpoints for EU/EMA regulatory purposes were asfollows:

1. Proportion of subjects with clinical remission per CDAI at Week 522. Proportion of subjects with endoscopic remission at Week 523. Change from Baseline in IBDQ at Week 524. Proportion of subjects achieving CR-100 at Week 525. Proportion of subjects without corticosteroid use for CD at least 90days prior to Week 52 and achieved clinical remission per PROs at Week52 (among all subjects)6. Proportion of subjects who discontinued corticosteroid use for CD atleast 90 days prior to Week 52 and achieved clinical remission per PROsat Week 52 in subjects taking corticosteroids for CD at Baseline ofinduction7. Proportion of subjects with clinical remission per PROs at Week 0 andWeek 528. Change from Baseline in FACIT-F at Week 529. Proportion of subjects with clinical remission per PROs andendoscopic remission at Week 5210. Proportion of subjects with CD-related hospitalizations during the52 Week double-blind maintenance period.11. Proportion of subjects with resolution of EIMs at Week 52, insubjects with EIMs at Baseline Ranked Secondary Endpoints for US/FDAregulatory purposes:1. Proportion of subjects with clinical remission per PROs at Week 522. Proportion of subjects achieving CR-100 at Week 523. Proportion of subjects with endoscopic remission at Week 524. Proportion of subjects without corticosteroid use for CD at least 90days prior to Week 52 and achieved clinical remission per CDAI at Week52 (among all subjects)5. Proportion of subjects with clinical remission per CDAI andendoscopic remission at Week 526. Proportion of subjects with clinical remission per CDAI at Week 0 andWeek 527. Proportion of subjects who discontinued corticosteroid use for CD atleast 90 days prior to Week 52 and achieved clinical remission per CDAIat Week 52, in subjects taking corticosteroids for CD at Baseline ofinduction8. Change from Baseline in IBDQ at Week 529. Change from Baseline in FACIT-F at Week 5210. Proportion of subjects with hospitalizations due to CD during the52-week doubleblind maintenance period11. Proportion of subjects with resolution of EIMs at Week 52, insubjects with EIMs at Baseline

Non-ranked endpoints were as follows:

Proportion of subjects with:

-   -   clinical remission per PROs and endoscopic remission at Week 52    -   clinical remission per PROs and endoscopic response at Week 52    -   clinical remission per CDAI and endoscopic remission at Week 52    -   clinical remission per CDAI and endoscopic response at Week 52    -   enhanced clinical response and endoscopic response at Week 52    -   clinical remission per PROs over time    -   enhanced clinical response over time    -   clinical response over time    -   clinical remission per CDAI over time    -   CR-100 over time    -   decrease in SES-CD>50% from Baseline of the induction study or        endoscopic remission at Week 52, as scored by central reviewer    -   with SES-CD≤2 at Week 52    -   with SES-CD ulcerated surface subscore of 0 at Week 52 in        subjects with SES-CD ulcerated surface subscore ≥1 at Baseline,        as scored by a central reviewer    -   with SES-CD ulcerated surface subscore ≤1 in each segment at        Week 52 in subjects with a SES-CD ulcerated surface subscore ≥2        at Baseline, as scored by a central reviewer    -   with endoscopic remission at Week 52 among subjects with SES-CD        subscore of 3 in the narrowing component at Week 52, which was        not present at Baseline    -   with endoscopic response at Week 52 among subjects with SES-CD        subscore of 3 in the narrowing component at Week 52, which was        not present at Baseline    -   with endoscopic response or endoscopic remission at Week 52        among subjects with SES-CD subscore of 3 in the narrowing        component at Week 52, which was not present at Baseline    -   with endoscopic remission at Week 52 among subjects with SES-CD        narrowing component subscore between 0 and 2 in all intestinal        segments at Baseline    -   with endoscopic response at Week 52 among subjects with SES-CD        narrowing component subscore between 0 and 2 in all intestinal        segments at Baseline    -   with endoscopic response or endoscopic remission at Week 52        among subjects with SES-CD narrowing component subscore between        0 and 2 in all intestinal segments at Baseline    -   with total hospitalizations (all-cause) during the 52-week        double-blind maintenance period    -   surgeries during the 52-week double-blind maintenance period    -   CD-related surgeries during the 52-week double-blind maintenance        period    -   who discontinue corticosteroid use for CD and achieve enhanced        clinical response at Week 52, in subjects taking corticosteroids        for CD at Baseline    -   who discontinue corticosteroid use for CD and achieve endoscopic        remission at Week 52, in subjects taking corticosteroids for CD        at Baseline    -   who discontinue corticosteroid use for CD and achieve endoscopic        response at Week 52, in subjects taking corticosteroids for CD        at Baseline    -   who discontinue corticosteroid use for CD at Week 0 and remained        corticosteroid-free through Week 52, in subjects taking        corticosteroids at Baseline    -   achieving Colonic and Ileal Global Histologic Disease Activity        Score (CGHAS/IGHAS) histologic remission (defined as CGHAS/IGHAS        score ≤3 in those with abnormal histology at Baseline) at Week        52    -   without draining fistulas at Week 52 in subjects with draining        fistulas at Week 0    -   with ≥50% reduction in draining fistulas at Week 52, in subjects        with draining fistulas at Baseline    -   with at least 50% decrease in the number of days with very soft        or liquid stools (Type 6 or 7, per Bristol Stool Chart) during        the last 7 days at Week 52.    -   with IBDQ remission (IBDQ>170 points) over time    -   with IBDQ response (increase in IBDQ>16 points from Baseline)        over time    -   achieving response in IBDQ fatigue item (increase of IBDQ        fatigue item score ≥1) over time.    -   achieving response in IBDQ Bowel Symptom domain (increase of        IBDQ bowel symptom domain score ≥8) at Week 52        Change from Week 0 in:    -   IBDQ over time    -   individual IBDQ domain scores (bowel, emotional, social,        systemic) over time    -   individual IBDQ item under Bowel Symptom domain (for Q1, Q5, Q9,        Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time    -   WPAI-CD over time    -   EQ-5D-5L over time    -   FACIT-F over time    -   SF-36 over time    -   CSS over time    -   average daily AP score over time    -   average daily very soft/liquid SF over time    -   FCP over time    -   hs-CRP over time    -   hs-CRP over time from Week 0 in subjects with hs-CRP≥5 mg/L at        Baseline of induction    -   SES-CD over time    -   mean CGHAS/IGHAS at Week 52 among subjects with abnormal        histology at Baseline        Change from Baseline (of induction) in:    -   IBDQ over time    -   Individual IBDQ domain scores (bowel, emotional, social,        systemic) over time    -   Individual IBDQ item under Bowel Symptom domain (for Q1, Q5, Q9,        Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time    -   WPAI-CD over time    -   EQ-5D-5L over time    -   FACIT-F over time    -   SF-36 over time    -   CSS over time    -   average daily AP score over time    -   average daily very soft/liquid SF over time    -   average daily total SF over time    -   FCP over time    -   hs-CRP over time    -   hs-CRP over time from Week 0 in subjects with hs-CRP≥5 mg/L at        Baseline of induction    -   SES-CD at Week 52 from Baseline/Week 0    -   mean CGHAS/IGHAS at Week 52 among subjects with abnormal        histology at Baseline

Time to:

-   -   clinical remission per PROs    -   clinical remission per CDAI    -   enhanced clinical response

Substudy 2 Efficacy Variables

Primary endpoint: Incidence of AEs over time

Additional efficacy endpoints are the following:Proportion of subjects

-   -   with clinical remission per PROs over time    -   with enhanced clinical response over time    -   with clinical response over time    -   with clinical remission per CDAI over time    -   with CR-100 over time    -   with endoscopic remission at Week 0, and every 48 weeks        thereafter    -   with endoscopic response at Week 0, and every 48 weeks        thereafter    -   with endoscopic remission at Week 0 and maintained at every 48        weeks thereafter    -   without corticosteroid use for CD and achieve clinical remission        per PROs over time    -   without corticosteroid use for CD and achieve clinical remission        per CDAI over time    -   without corticosteroid use for CD over time    -   with clinical remission per PROs over time who were in clinical        remission per PROs at Week 0    -   achieving IBDQ response (increase of IBDQ≥16 over time)    -   who required rescue therapy and achieved clinical response over        time    -   who required rescue therapy and achieved clinical remission per        PROs over time    -   with draining fistulas over time in subjects with draining        fistulas at Baseline of induction study    -   resolution of EIMs over time in subjects with EIMs at Baseline        of induction    -   total hospitalizations (all-cause) over time    -   with CD-related hospitalizations over time    -   surgeries over time    -   CD-related surgeries over time        Time to loss of    -   enhanced clinical response    -   clinical remission per PROs    -   clinical remission per CDAI        Change from Baseline in    -   hs-CRP over time    -   FCP over time    -   average daily total SF over time    -   average daily AP score over time    -   average daily very soft/liquid SF over time    -   CDAI over time    -   IBDQ score over time    -   EQ-5D score over time    -   WPAI scores over time    -   SF-36 score over time    -   FACIT-F score over time    -   SES-CD over time        Change from Week 0 in    -   hs-CRP over time    -   FCP over time    -   average daily total SF over time    -   average daily AP score over time    -   average daily very soft/liquid SF over time    -   CDAI over time    -   IBDQ score over time    -   EQ-5D score over time    -   WPAI scores over time    -   SF-36 score over time    -   FACIT-F score over time    -   SES-CD over time

Method of Assigning Subjects to Treatment Groups Substudy 1

The IRT assigned a randomization number that encoded the subject'streatment group assignment according to the randomization schedulegenerated by the Statistics Department at AbbVie. IRT provided theappropriate medication kit number(s) to dispense to each subject. InCohort 1, subjects (approximately n=537) were randomized in a 1:1:1ratio to upadacitinib 15 mg QD, upadacitinib 30 mg QD, or matchingplacebo for 52 weeks (FIG. 52). The randomization wad stratified byprior induction study population (1) Study M14-433 non-bio-IR, 2) StudyM14-433 bio-IR or Study M14-431 Part 1/Part 3, 3) Study M14-431 Part 2),clinical remission per PROs status (yes or no), and endoscopic responsestatus (yes or no; based on the local read) at Week 12 or 24 of StudyM14-431 or Study M14-433. In Cohorts 2 and 3, subjects were assigned byIRT to continue to receive blinded placebo or blinded upadacitinib,respectively, until Week 52.

Substudy 2

In Cohort 4, subjects continued to receive open-label upadacitinib 30 mgQD for 240 weeks.

In Cohort 5, all subjects receiving upadacitinib continued to receivetheir originally assigned double-blind treatment (upadacitinib 30 mg QD,or upadacitinib 15 mg QD). The subjects receiving placebo only receivedthe concomitant CD-related medications, if any. The treatmentassignments were unblinded when the last subject in Substudy 1 completedWeek 52.

Selection and Timing of Dose for Each Subject

On dosing days that occured on study visit days, subjects followed theregular dosing schedule. Each subject's dosing schedule was closelymonitored by the site at each study visit. This ensured that allsubjects enrolled into the study maintained their original dosingschedule beginning with the first dose of study drug (Week 0/Day 1). Ifa subject forgot to take upadacitinib (or matching placebo) dose attheir regularly scheduled dosing time, they took the forgotten dose assoon as they remembered the dose was missed as long as it was at least10 hours before their next scheduled dose. If a subject only rememberedthe missed dose within 10 hours before next scheduled dose, the subjectcould skip the missed dose and take the next dose at the scheduled time.For elective and emergency surgeries, the following rules applied:

-   -   If the subject underwent emergency surgery, the study drug was        interrupted at the time of the surgery. After emergency surgery,        reintroduction of study drug was allowed once the physician had        examined the surgical site and determined that it had healed and        there was no sign of infection.    -   Elective surgery was not allowed during the study until the        primary endpoint had been assessed. If the subject underwent        elective surgery, the study drug was interrupted 1 week prior to        the planned surgery. Reintroduction of study drug was allowed        once the physician had examined the surgical site and determined        that it had healed and there was no sign of infection.

Discussion of Study Design and Choice of Control Groups

This study included two substudies:

-   -   Substudy 1 was a 52-week, randomized, double-blind, maintenance        substudy that includes three cohorts. Cohort 1 evaluated the        efficacy and safety of two doses of upadacitinib versus placebo        as maintenance therapy in subjects with moderately to severely        active CD who responded to upadacitinib induction treatment in        Study M14-431 or Study M14-433. A comparative study utilizing        placebo provided an unbiased assessment of the efficacy and        safety profile of upadacitinib during maintenance treatment in        subjects who responded to the induction treatment. Cohorts 2 and        3 enrolled subjects who achieved clinical response to placebo or        from the Extended Treatment Period with upadacitinib,        respectively. These two cohorts maintained the treatment        received in the induction studies in a blinded manner and did        not have a control group.    -   The purpose of Substudy 2 was to evaluate the safety and        efficacy of long-term administration of upadacitinib in subjects        who participated in the Phase 3 upadacitinib induction and        maintenance studies. During the follow up, subjects receiving        placebo were used as a reference group, for the descriptive        analyses of the safety and efficacy.

Selection of Doses in the Study

This study evaluated two maintenance doses of upadacitinib at 15 mg and30 mg QD. The selection of these doses was informed by the analysis ofthe 16-week safety, efficacy, and exposure-response data of StudyM13-740, a Phase 2 study in subjects with moderately to severely activeCD that explored five induction doses of upadacitinib using theimmediate-release formulation (3, 6, 12, or 24 mg BID or 24 mg QD)versus placebo. In addition, all the currently available PK,pharmacodynamic, safety, and efficacy data from upadacitinib studieswere used to support the selection of these doses. The induction phaseresults from Study M13-740 demonstrated the clinical and endoscopicefficacy of upadacitinib compared to placebo with doses of 6 mg BID andhigher. The doses of 15 mg QD and 30 mg QD using the once-dailyformulation provide equivalent daily area under the concentration-timecurve (AUC) and comparable minimum plasma concentration (C_(min)) andmaximum plasma concentration (Cmax) to 6 mg BID and 12 mg BID,respectively, using the immediate-release formulation. Followinginduction with 45 mg QD, doses of 15 mg QD and 30 mg QD are expected tomaintain clinical and endoscopic response while having better long-termsafety profile compared to higher doses. Doses of 15 mg QD and 30 mg QDfor up to 240 weeks were expected to be efficacious with an acceptablesafety profile.

Adverse Events of Special Interest

The following AEs of special interest will be monitored during thestudy: Serious infections; Opportunistic infections; Herpes zoster;Active TB; Malignancy (all types); Adjudicated gastrointestinalperforations; Adjudicated cardiovascular events (e.g., major adversecardiac event [MACE]); Anemia; Neutropenia; Lymphopenia; Renaldysfunction; Hepatic disorder; Elevated CPK; Adjudicated embolic andthrombotic events (non-cardiac, non-central nervous system [CNS]).

Toxicity Management

The toxicity management of the AEs including AEs of special interestconsisted of safety monitoring (review of AEs on an ongoing basis, andperiodical/ad hoc review of safety issues by a safety data monitoringcommittee), interruption of study drug dosing with appropriate clinicalmanagement if applicable, and discontinuation of the subjects from studydrug. The management of specific AEs and laboratory parameters isdescribed below. For subjects who discontinued study drug but continuedstudy participation and were on standard of care therapies, thesetoxicity management requirements did not apply (including alerts fromthe central lab) and any intolerability to standard of care therapieswas managed by the prescribing physician.

Serious Infections

Subjects were closely monitored for the development of signs andsymptoms of infection during and after treatment with study drug. Studydrug was interrupted if a subject developed a serious infection. Asubject who developed a new infection during treatment with study drugunderwent prompt diagnostic testing appropriate for an immunocompromisedsubject. As appropriate, antimicrobial therapy was initiated, and thesubject closely monitored. Study drug was resumed once the infection hadbeen successfully treated. Subjects who developed active TB werediscontinued from study drug.

Herpes Zoster:

If a subject developed herpes zoster, temporarily interrupting studydrug until the episode resolves was considered.

Gastrointestinal Perforation:

Subjects presenting with the onset of signs or symptoms of agastrointestinal perforation were evaluated promptly for early diagnosisand treatment. If the diagnosis of gastrointestinal perforation wasconfirmed (other than appendicitis or mechanical injury), the subjectwas discontinued from study drug.

Cardiovascular Events (MACE):

Subjects presenting with potential cardiovascular events wereappropriately assessed and carefully monitored. These events werereviewed and adjudicated by an independent CAC in a blinded manner.

Thrombosis Events:

Subjects who developed symptoms of thrombosis were promptly evaluatedand treated appropriately. If the diagnosis of deep vein thrombosis,pulmonary embolus, nonneurologic, non-cardiac arterial thrombosis wasconfirmed, the subject was discontinued from the study drug.

COVID-19:

Study drug in subjects with a confirmed diagnosis of COVID-19 wasinterrupted. Interruption of study drug in subjects with signs and/orsymptoms and suspicion of COVID-19 was considered. Malignancy:

Subjects who developed malignancy or high-grade colonic dysplasia, otherthan NMSC or carcinoma in situ of the cervix were discontinued fromstudy drug. Periodic skin examination was recommended for subjects whowere at increased risk for skin cancer.

ECG Abnormality:

Subjects were discontinued from study drug for an ECG change consideredclinically significant and with reasonable possibility of relationshipto study drug, OR a confirmed absolute QTcF value >500 msec.

Management of Select Laboratory Abnormalities:

For any given laboratory abnormality, the investigator assessed thesubject, applied the standard of care for medical evaluation andtreatment followed any local guidelines. Specific toxicity managementguidelines for abnormal laboratory values are described in Table 45. Allabnormal laboratory tests that were considered clinically significant bythe investigator were followed to satisfactory resolution. If a repeattest was required per Table 45, the repeat testing occurred as soon aspossible.

TABLE 45 Specific Toxicity Management Guidelines for Abnormal LaboratoryValues Laboratory Parameter Toxicity Management Guideline Hemoglobin Ifhemoglobin <8 g/dL interrupt study drug dosing and confirm by repeattesting with a new sample. If hemoglobin decreases ≥3.0 g/dL from Week 0without an alternative etiology, interrupt study drug dosing and confirmby repeat testing with new sample. If hemoglobin decreases ≥3.0 g/dLfrom Week 0 and an alternative etiology is known, or the hemoglobinvalue remains in the normal reference range, the subject may remain onstudy drug at the investigator's discretion. If confirmed, continue towithhold study drug until hemoglobin value returns to normal referencerange or its Week 0 value. ANC If confirmed <1000/μL by repeat testingwith new sample, interrupt study drug dosing until ANC value returns tonormal reference range or its Week 0 value. Interrupt study drug ifconfirmed <500/μL by repeat testing with new sample. If value returns tonormal reference range or its Baseline value, restarting study drug isallowed if there is an alternative etiology identified; documentationshould include reason rechallenge is expected to be safe for thesubject. Study drug should be discontinued if no alternative etiologycan be found. ALC If confirmed <500/μL by repeat testing with newsample, interrupt study drug dosing until ALC returns to normalreference range or its Week 0 value. Total WBC If confirmed <2000/μL byrepeat testing count with new sample, interrupt study drug dosing untilWBC count returns to normal reference range or its Week 0 value.Platelet count If confirmed <50,000/μL by repeat testing with newsample, interrupt study drug dosing until platelet count returns tonormal reference range or its Week 0 value AST or ALT Interrupt studydrug if confirmed ALT or AST >3 × ULN by repeat testing with new sampleand either a total bilirubin >2 × ULN or an international normalizedratio (INR) >1.5. A separate blood sample for INR testing will be neededto measure INR at the time of repeat testing for ALT or AST. A repeattest of INR is not needed for determination if above toxicity managementcriteria are met. Interrupt study drug if confirmed ALT or AST >3 × ULNby repeat testing with new sample along with new appearance of fatigue,nausea, vomiting, right upper quadrant pain or tenderness, fever, rash,and/or eosinophilia (>5% increase from Baseline). Interrupt study drugif confirmed ALT or AST >8 × ULN by repeat testing with new sample.Interrupt study drug if confirmed ALT or AST >5 × ULN by repeat testingwith new sample for more than 2 weeks. For subjects with positive HBc Ab(irrespective of HBs Ab status) and negative HBV DNA at screening whodevelop the following laboratory findings should have HBV DNA by PCRtesting should be performed within 1 week (based on initial elevatedvalue): ALT >5 × ULN OR ALT/AST >3 × ULN, if an alternative cause is notreadily identified A separate blood sample for HBV DNA by PCR testingwill be needed at the time of repeat testing for ALT or AST. A positiveresult for HBV DNA PCR testing in these subjects will require immediateinterruption of study drug and a hepatologist consultation should occurwithin 1 week for recommendation regarding subsequent treatment.Subjects who meet any of the above criteria should be evaluated for analternative etiology of the ALT or AST elevation and managed asmedically appropriate. The investigator should contact the AbbVie TA MDto discuss the management of a subject when an alternative etiology hasbeen determined. The alternative etiology should be documentedappropriately in the eCRF; study drug should be discontinued if noalternative etiology can be found and ALT or AST elevations persist. IfALT or AST values return to the normal reference range or its Baselinevalue, study drug may be restarted. If restarting study drug,documentation should include reason rechallenge is expected to be safe.Serum If serum creatinine is >1.5 × the Week 0 creatinine valueand >ULN, repeat the test for serum creatinine (with subject in aeuvolemic state) to confirm the results. If the results of the repeattesting still meet this criterion then interrupt study drug and restartstudy drug once serum creatinine returns to ≤1.5 × Week 0 value and≤ULN. CPK If any confirmed CPK value ≥4 × ULN (if symptomatic orasymptomatic). If confirmed CPK ≥4 × ULN accompanied by symptomssuggestive of myositis or rhabdomyolysis, interrupt study drug

Datasets for Analysis Intent-to-Treat Analysis Set

The intent-to-treat analysis set (ITT1) for Substudy 1 Cohort 1 was toinclude the first randomized subjects, approximately 501, who receivedat least one dose of study drug in the double-blind maintenance period.The intent-to-treat (ITT) analysis set for Substudy 1 Cohort 2 andCohort 3 was to include all enrolled subjects who received at least onedose of study drug in the double-blind maintenance period. The ITT andITT1 subjects were to be analyzed as randomized. The ITT1 set was to bethe primary population for efficacy analysis in Substudy 1. The ITTanalysis set for Substudy 2 was to include all subjects who received atleast one dose of study drug in the LTE period. The ITT set was to bethe primary population for efficacy analysis in Substudy 2.

Safety Analysis Set

The safety analysis set was to consist of all subjects who received atleast one dose of the study drug. The safety analysis set was to beanalyzed as treated, according to treatment the subject actuallyreceived. The safety analysis set was used for safety analysis.

Substudy 1: Was to include all subjects who received at least one doseof study drug in the double-blind maintenance period of the study(including nonrandomized subjects).

Substudy 2: Was to include all subjects who received at least one doseof study drug in the LTE phase of the study.

Randomization Methods

Approximately 427 subjects who received upadacitinib 45 mg QD inductiontreatment for 12 weeks in Study M14-431 (from Part 1 or Part 2) or StudyM14-433 (Part 1), and approximately 110 subjects who receivedupadacitinib 45 mg QD induction treatment for 12 weeks during theExtended Treatment Period of Study M14-431 (Cohort 1 of Part 3) or StudyM14-433 (Cohort 1 of Part 2) and achieved clinical response were to bere-randomized in a 1:1:1 ratio to one of the following three treatmentgroups:

-   -   Group 1: Upadacitinib 15 mg    -   Group 2: Upadacitinib 30 mg    -   Group 3: Placebo

The randomization was to be stratified by prior induction studypopulation (1) Study M14-433 non-bio-IR, 2) Study M14-433 bio-IR orStudy M14-431 Part 1/Part 3, 3) Study M14-431 Part 2), clinicalremission per PROs status (yes or no), and endoscopic response status(yes or no; based on the local read) at Week 12 or 24 of Study M14-431or Study M14-433. Subjects enrolling in Cohorts 2 and 3 of this studywere assigned placebo and upadacitinib 30 mg QD, respectively, in ablinded fashion. Subjects enrolled into Cohort 4 in an open-labelmanner. Subjects enrolling into Cohort 5 were assigned placebo orupadacitinib 30 mg QD or upadacitinib 15 mg QD in a blinded fashion,according to the randomized treatment received in Substudy 1.

Patient Reported Outcomes Descriptions IBDQ—Inflammatory Bowel DiseaseQuestionnaire

The IBDQ is a disease-specific instrument composed of 32 Likert-scaleditems. The total score ranges from 32 to 224 using the 7-point responseoptions, with higher scores indicating better health-related quality oflife. The IBDQ scale contains 4 component subscales: bowel symptoms,systemic symptoms, emotional function, and social function. Eachsubscale can be computed with total scores ranging from 10-70, 5 to 35,12 to 84, and 5 to 35, respectively.

WPAI-CD—Work Productivity and Activity Impairment Questionnaire—Crohn'sDisease

The Work Productivity and Activity Index assesses the impact of thecondition on work productivity losses and impairment in daily activity.WPAI has six items covering four domains: Absenteeism (work timemissed), measured as the number of hours missed from work in the past 7days due to condition related problems. Scores are expressed asimpairment percentages, adjusting for hours actually worked according tothe WPAI scoring algorithm; Presenteeism (impairment at work/reducedon-the-job effectiveness), measured as the impact of the condition onproductivity while at work (i.e., reduced amount or kind of work, or notas focused as usual). Responses are recorded on a 0-10 Likert scale(where, 0=no effect of CD on work and 10=severe impact of CD while atwork); productivity loss (overall work impairment), measured as the sumof hours missed due to condition i.e., absenteeism and number of hoursworked with impairment i.e., product of number of hours worked andpresenteeism; and activity impairment (i.e., activities other than paidwork like work around house, cleaning, shopping, traveling, studying),recorded and scored in same way as presenteeism. Higher numbers indicategreater impairment and less productivity.

CSS—Crohn's Symptoms Severity Questionnaire

The CSS questionnaire is a 14-item assessment of both GI and non-GI CDsymptoms using a 7-day recall period. The 14 items assess the frequencyor intensity of each individual symptom by utilizing a 5-pointLikert-type scale. An assessment of an individual items frequency andintensity is measured as follows:

-   -   Frequency: 1=Never, 2=Rarely, 3=Sometimes; 4=Often, 5=Always    -   Intensity: 1=Not at all, 2=A little bit; 3=Somewhat; 4=Quite a        bit; 5=Very much        An overall symptom score is calculated by combining ratings from        the 14 individual items (possible scores range from 14 to 70)        with higher scores indicating greater symptom frequency or        intensity.

SF-36—Short Form 36

The SF-36 questionnaire is a self-administered multi-domain scale with36 items. Eight subscales cover a range of functioning: physicalfunctioning, role-physical, bodily pain, general health, vitality,social functioning, role-emotional, and mental health. The scoringyields a physical component score, a mental component summary score, andsubscale scores. Higher scores represent better outcomes. The conceptsmeasured by the SF-36 are not specific to any age, disease, or treatmentgroup, allowing comparison of relative burden of different diseases andthe benefit of different treatments.

EQ-5D—European Quality of Life 5 Dimensions

The EQ-5D-5L is a standardized non-disease specific instrument fordescribing and valuing health-related quality of life. The EQ-5Dconsists of 5 dimensions: mobility, self care, usual activity,pain/discomfort, and anxiety/depression. Each dimension has 5 levels: noproblem, slight problem, moderate problem, severe problem or unable todo the activity. It also contains a Visual Analogue Scale (VAS).Subjects are asked to indicate the level that describes their currentlevel of function or experience for each dimension. As a measure ofhealth status, it provides a descriptive profile and can be used togenerate a single index value for health status, where full health isequal to 1 and death is equal to 0. The VAS records the subject'sassessment of his/her own health along a vertical 20 cm line, which hashealth state scores between 0 and 100.

FACIT-F—Functional Assessment of Chronic Illness Therapy-Fatigue

The FACIT system is a collection of quality of life (QoL) questionnairestargeted to the management of cancer and other chronic illnesses. TheFACIT fatigue (FACIT-F) questionnaire was developed to assess fatigueassociated with anemia. It consists of 13 fatigue-related questions. Theresponses to the 13 items on the FACIT fatigue questionnaire are eachmeasured on a 4-point Likert scale. The responses to the answers are thefollowing: (i) not at all: 0 points; (ii) a little bit: 1 point; (iii)somewhat: 2 points; (iv) quite a bit: 3 points; (v) very much: 4 points.Thus, the total score ranges from 0 to 52. High scores represent lessfatigue.

PGIC—Patient Global Impression of Change

The PGIC is a self-administered instrument that assesses change in theoverall symptoms due to Crohn's disease. The PGIC is one item in whichsubjects are asked to rate overall improvement since start of thetreatment. Subjects rate their change as “Very much improved,” “Muchimproved,” “Minimally improved,” “No change,” “Minimally worse,” “Muchworse” and “Very much worse.”

PGI-S—Patient Global Impression of Severity

The PGI-S is a self-administered instrument that assesses the severityof the overall symptoms due to Crohn's disease. The PGI-S is one item inwhich subjects are asked to rate overall severity of symptoms over thepast week. Subjects rate their change as “Absent,” “Minimal,” “Mild,”“Moderate,” “Moderately severe,” “Severe” and “Very severe.”

Corticosteroid Taper Schedule

At Week 0, all subjects who were taking steroids at Baseline of StudyM14-431 or Study M14-433 and had not completed the corticosteroid taper,continued the mandatory taper schedule outlined in FIGS. 54 and 55.

Results

Study M14-430 was a Phase 3 maintenance and long-term extension (LTE)study to evaluate the maintenance and long-term safety and efficacy ofupadacitinib (UPA) in subjects with moderately to severely activeCrohn's disease (CD) who have completed induction studies M14-431 orM14-433. At Week 0, all subjects who achieved clinical response (definedas ≥30% decrease in average daily very soft or liquid SF and/or ≥30%decrease in average daily AP score, with both SF and AP not worse thanBaseline) at the end of the Induction Studies M14-431 or M14-433 were toenroll in Sub-study 1 and to receive study drug in a blinded fashion.

This study contained two sub-studies: Sub-study 1 included a 52-weekMaintenance Period, and Sub-study 2 included a 240-week LTE Period.Sub-study 1 contained 3 cohorts.

Cohort 1: Subjects who received the 12-week induction treatment with UPA45 mg and achieved clinical response in studies M14-431 or M14-433 wererandomized to receive double-blind UPA 30 mg, UPA 15 mg, or placebo(PBO) in a 1:1:1 ratio. The randomization was stratified by bio-IR andnon-bio-IR status in the induction studies, as well as the clinicalremission (per PROs) and endoscopic response status at the entry ofM14-430 Sub-study 1. According to the protocol, all primary andsecondary efficacy endpoints were analyzed among the ITT1 Population,which included the first approximately 501 subjects* who were randomizedand received at least one dose of study drug. The actual number ofsubjects included in the ITT1 Population was 502,

Cohort 2: Subjects who received the 12-week induction treatment with PBOand achieved clinical response in studies M14-431 or M14-433 continuedto receive double-blind PBO.

Cohort 3: Subjects who initially did not achieve clinical response afterthe 12-week induction treatment with UPA 45 mg, received the 12-weekextended treatment with UPA 30 mg and achieved clinical response instudies M14-431 or M14-433, continued to receive double-blind UPA 30 mg.

Starting from Week 4, subjects who met the criteria for inadequateresponse had the option to receive rescue therapy with open label (OL)UPA 30 mg QD from that point forward. Subjects would be considered asnon-responders after being rescued.

A total of 674 subjects were randomized (223 in PBO, 221 in UPA 15 mg,and 230 in UPA 30 mg) in Cohort 1 of Sub-study 1, 673 received at leastone dose of study drug. Among these subjects, 502 were randomized on orprior to Mar. 29, 2021; and were included in the Primary Analysis forefficacy (i.e., the ITT1 Population).

In the ITT1 Population, a total of 381 (75.9%) subjects completed thestudy drug in Sub-study 1 (Table 46). Among these, higher proportion ofsubjects from the PBO group received the rescue treatment withopen-label UPA 30 mg. Baseline demographics and disease characteristicswere generally balanced between treatment groups.

TABLE 46 Subject Disposition in Sub-study 1 (ITT1 Population) SubjectPBO UPA 15 mg UPA 30 mg Total Disposition, n (%) (N = 165) (N = 169) (N= 168) (N = 502) Completed Study Drug 122 (73.9) 125 (74.0) 134 (79.8)381 (75.9) Without Receiving OL Rescue, UPA 30 mg QD 45 (27.3) 88 (52.1)105 (62.5) 238 (47.4) After Receiving OL Rescue, UPA 30 mg QD 77 (46.7)37 (21.9) 29 (17.3) 143 (28.5) Discontinued Study Drug¹ 43 (26.1) 44(26.0) 34 (20.2) 121 (24.1) Without Receiving OL Rescue, 18 (10.9) 23(13.6) 20 (11.9) 61 (12.2) UPA 30 mg QD Adverse event 6 (3.6) 10 (5.9)10 (6.0) 26 (5.2) Withdrawal by subject 4 (2.4) 4 (2.4) 7 (4.2) 15 (3.0)Lost to follow-up 1 (0.6) 2 (1.2) 1 (0.6) 4 (0.8) Lack of efficacy 6(3.6) 5 (3.0) 1 (0.6) 12 (2.4) COVID-19 infection 0 0 0 0 COVID-19logistical restrictions 0 0 0 0 Other 1 (0.6) 2 (1.2) 1 (0.6) 4 (0.8)After Receiving OL Rescue, UPA 30 mg QD 25 (15.2) 21 (12.4) 14 (8.3) 60(12.0) Adverse event 4 (2.4) 6 (3.6) 3 (1-8) 13 (2.6) Withdrawal bysubject 1 (0.6) 3 (1.8) 2 (1.2) 6 (1.2) Lost to follow-up 1 (0.6) 1(0.6) 0 2 (0.4) Lack of efficacy 17 (10.3) 9 (5.3) 9 (5.4) 35 (7.0)COVID-19 infection 0 0 0 0 COVID-19 logistical restrictions 0 0 0 0Other 2 (1.2) 2 (1.2) 0 4 (0.8) ¹Summarized by primary reason ofdiscontinuation.

Efficacy

The study has different sets of co-primary endpoints and key secondaryendpoints for EU/EMA and US/FDA regulatory purposes. Under eitherstrategy, the overall type-I error rate is strongly controlled with a2-sided alpha level of 0.05. Co-primary endpoints were achieved for bothEU/EMA (Table 47) and US/FDA (Table 48) regulatory purposes,demonstrating the superiority of both UPA 30 mg vs. PBO and UPA 15 mgvs. PBO, with p<0.0001. Consistent efficacy results for co-primaryendpoints were observed among subgroups of non-bio-IR/bio-IR subjects,as well as in the sensitivity analyses. In addition, 10 out of 11 keysecondary endpoints for UPA 30 mg vs. PBO and 8 out of 11 for UPA 15 mgvs. PBO were achieved, according to the pre-defined strategy for overalltype-I error control.

TABLE 47 Primary and Key Secondary Endpoints for EU/EMA RegulatoryPurposes (ITT1 Population) UPA 15 mg UPA 30 mg PBO (N = 169) (N = 168)(N = 165) Adj. Diff Adj. Diff Endpoint¹ Estimate Estimate [95% CI]p-value² Estimate [95% CI] p-value² Co-Priniary Endpoints Clinicalremission per 14.4 35.5 21.9 [13.7, <.0001^(S) 46.4 31.8 [23.2,<.0001^(S) PROs, (%) 30.0] 40.3] Endoscopic response,  7.3 27.6 21.0[13.6, <.0001^(S) 40.1 33.7 [26.0, <.0001^(S) (%) 28.4] 41.3] KeySecondary Endpoints Clinical remission per 15.1 37.3 23.7 [15.2,<.0001^(S) 47.6 32.8 [23.9, <.0001^(S) CDAI, (%) 32.1] 41.6] Endoscopicremission,  5.5 19.1 14.4 [7.7 <.0001^(S) 28.6 23.6 [16.1, <.0001^(S)(%) 21.0] 31.0] Change from BL in (N = 41) (N = 78) 12.9 [4.3,0.0033^(S) (N = 94) 18.1 [9.8, <.0001^(S) IBDQ, (LS Mean) 46.4 59.321.4] 64.5 26.4] CR-100, (%) 15.2 41.4 27.1 [18.3, <.0001^(S) 51.2 36.4[ 27.5, <.0001^(S) 35.8] 45.2] Steroid-free clinical 14.4 34.9 21.3[13.1, <.0001^(S) 44.6 30.0 [21.4, <.0001^(S) remission per PROs, 29.5]38.6] among all subjects, (%) Steroid-free clinical (N = 61) (N = 63)33.0 [20.4, <.0001^(S) (N = 63) 33.6 [21.4, <.0001^(S) remission perPROs,  4.9 38.1 45.6] 38.1 45.8] among subjects w. steroid for CD at BL,(%) Maintenance of clinical (N = 101)  (N = 105)  31.9 [20.1, <.0001^(S)(N = 105) 39.7 [27.8, <.0001^(S) remission per PROs, (%) 19.6 50.5 43.6]60.0 51.7] Change from BL in (N = 40) (N = 78) 2.3 [−0.6, 0.1149^(NS) (N= 94) 4.1 [1.3, 0.0039^(S) FACIT-F, (LS Mean) 12.0 14.3 5.2] 16.1 6.9]Clinical remission per  4.3 13.7 10.0 [4.0, 0.0011^(S) 22.6 18.2 [11.3,<.0001^(S) PROs and endoscopic 16.0] 25.0] remission, (%) Occurrence ofCD- 12.0 11.2 −0.8 [−10.4, 0.8742^(NS)  7.8 −4.2 [−13.1, 0.3570^(NS)related hospitalization, 8.8] 4.7] (n/100 PYs) Resolution of EIMs, (%)(N = 66) (N = 61) 9.6 [−3.4, 0.1476^(NS) (N = 73) 22.0 [9.3, 0.0007^(S)15.2 24.6 22.6] 35.6 34.8] Note: Among intent-to-treat population forPart 1 (ITT1), defined as all subjects who were randomized and receivedat least one dose of study drug on or prior to Mar. 29, 2021, inSub-study 1. BL: Baseline. CI: Confidence interval. LS: Least Square.PBO: Placebo. UPA: Upadacitinib. Missing data were imputed usingNon-Responder Imputation (NRI) while incorporating Multiple Imputation(MI) to handle missing data due to COVID-19 (NRI-C) for categoricalendpoints; except for the occurrence of hospitalization, which wassummarized based on as-observed data. For continuous endpoints, missingdata were handled using Mixed-effect Model Repeat Measurement (MMRM) forcontinuous endpoints. ¹All co-primary and key secondary endpoints areassessed at Week 52, except for the occurrence of CD-relatedhospitalization, which is summarized by the exposure-adjusted incidencerate during Sub-study 1. ²P-value for treatment difference between UPA30 mg (or 15 mg) and PBO. S/NS: Achieved/not achieved statisticalsignificance according to the pre-specified testing strategy for overalltype I error control

TABLE 48 Primary and Key Secondary Endpoints for US/FDA RegulatoryPurposes (ITT1 Population) UPA 15 mg UPA 30 mg PBO (N = 169) (N = 168)(N = 165) Adj. Diff Adj. Diff Endpoint¹ Estimate Estimate [95% CI]p-value² Estimate [95% CI] p-value² Co-Primary Endpoints Clinicalremission 15.1 37.3 23.7 [15.2, <.0001^(S) 47.6 32.8 [23.9, <.0001^(S)per CDAI, (%) 32.1] 41.6] Endoscopic  7.3 27.6 21.0 [13.6, <.0001^(S)40.1 33.7 [26.0, <.0001^(S) response, (%) 28.4] 41.3] Key SecondaryEndpoints Clinical remission 14.4 35.5 21.9 [13.7, <.0001^(S) 46.4 31.8[23.2, <.0001^(S) per PROs, (%) 30.0] 40.3] CR-100, (%) 15.2 41.4 27.1[18.3, <.0001^(S) 51.2 36.4 [27.5, <.0001^(S) 35.8] 45.2] Endoscopic 5.5 19.1 14.4 [7.7, <.0001^(S) 28.6 23.6 [16.1, <.0001^(S) remission,(%) 21.0] 31.0] Steroid-free clinical 14.5 36.7 23.8 [15.5, <.0001^(S)46.4 32.2 [23.4, <.0001^(S) remission per CDAI, 32.1] 40.9] among allsubjects, (%) Clinical remission  3.7 14.8 12.2 [6.3, .0001^(S) 23.219.8 [13.0, <.0001^(S) per CDAI and 18.1] 26.6] endoscopic remission,(%) Maintenance of (N = 94) (N = 101)  31.6 [19.6, <.0001^(S) (N = 92)43.4 [31.4, <.0001^(S) clinical remission 21.2 49.5 43.6] 65.2 55.5] perCDAI, (%) Steroid-free clinical (N = 61) (N = 63) 35.4 [23.3, <.0001^(S)(N = 63) 32.3 [20.1, <.0001^(S) remission per CDAI,  4.9 39.7 47.5] 39.744.5] among subjects w. steroid for CD at BL, (%) Change from BL in (N =41) (N = 78) 12.9 [4.3, 0.0033^(S) (N = 94) 18.1 [9.8, <.0001^(S) IBDQ,(LS Mean) 46.4 59.3 21.4] 64.5 26.4] Change from BL in (N = 40) (N = 78)2.3 [−0.6, 0.1149^(NS) (N = 94) 4.1 [1.3, 0.0039^(S) FACIT-F, (LS Mean)12.0 14.3 5.2] 16.1 6.9] Occurrence of CD- 12.0 11.2 −0.8 [−10.4,0.8742^(NS)  7.8 −4.2 [−13.1, 0.3570^(NS) related hospitalization, 8.8]4.7] (n/100 PYs) Resolution of EIMs, (%) (N = 66) (N = 61) 9.6 [−3.4,0.1476^(NS) (N = 73) 22.0 [9.3, 0.0007^(S) 15.2 24.6 22.6] 35.6 34.8]Note: Among intent-to-treat population for Part 1 (ITT1), defined as allsubjects who were randomized and received at least one dose of studydrug on or prior to Mar. 29, 2021, in Sub-study 1. BL: Baseline. CI:Confidence interval. LS: Least Square. PBO: Placebo. UPA: Upadacitinib.Missing data were imputed using Non-Responder Imputation (NRI) whileincorporating Multiple Imputation (MI) to handle missing data due toCOVID-19 (NRI-C) for categorical endpoints; except for the occurrence ofhospitalization, which was summarized based on as-observed data. Forcontinuous endpoints, missing data were handled using Mixed-effect ModelRepeat Measurement (MMRM) for continuous endpoints. ¹All co-primary andkey secondary endpoints are assessed at Week 52, except for theoccurrence of CD-related hospitalization, which is summarized by theexposure-adjusted incidence rate during Sub-study 1. ²P-value fortreatment difference between UPA 30 mg (or 15 mg) and PBO. S/NS:Achieved/not achieved statistical significance according to thepre-specified testing strategy for overall type-I error control.

EU/EMA:

Achievement of clinical remission per patient-reported outcomes (PROs)at Week 52: Both UPA 30 mg (46.4%) and UPA 15 mg (35.5%) showedsuperiority vs. PBO (14.4%); with p<0.0001. (FIG. 56A). Note: clinicalremission per PROs is defined as average daily very soft/liquid stoolfrequency (SF)≤2.8 & average daily abdominal pain (AP) score ≤1.0, withboth SF & AP not worse than Baseline. FIG. 56B provides results forplacebo, UPA 15 mg, and UPA 30 mg for clinical remission per CDAI(CDAI<150).

Achievement of endoscopic response at Week 52: Both UPA 30 mg (40.1%)and UPA 15 mg (27.6%) showed superiority vs. PBO (7.3%); with p<0.0001(FIG. 56C). Note: endoscopic response is defined as >50% decrease inSimple Endoscopic Score for Crohns Disease (SES-CD; centrally read) fromBaseline (or ≥2-point decrease for subjects with a Baseline SES-CD of4).

US/FDA:

Achievement of clinical remission per Crohn's Disease Activity Index(CDAI) at Week 52: Both UPA 30 mg (47.6%) and UPA 15 mg (37.3%) showedsuperiority vs. PBO (15.1%); with p<0.0001. Note, clinical remission perCDAI is defined as CDAI<150.

Achievement of endoscopic response at Week 52: Both UPA 30 mg (40.1%)and UPA 15 mg (27.6%) showed superiority vs. PBO (7.3%); with p<0.0001.

In addition, 10 out of 11 key secondary endpoints for UPA 30 mg vs. PBOand 8 out of 11 for UPA 15 mg vs. PBO were achieved, according to thepre-defined strategy for overall type-I error control, for both EU/EMAand US/FDA regulatory purposes.

Additional Efficacy Results

The proportion of subjects achieving clinical remission per PRO forplacebo, upadacitinib 15 mg QD, and upadacitinib 30 mg QD innon-biologic-inadequate responders (Non-Bio-IR) and biologic-inadequateresponders (Bio-IR) is provided in FIG. 57A.

The proportion of subjects achieving clinical remission per CDAI forplacebo, upadacitinib 15 mg QD, and upadacitinib 30 mg QD innon-biologic-inadequate responders (Non-Bio-IR) and biologic-inadequateresponders (Bio-IR) is provided in FIG. 57B.

The proportion of subjects achieving endoscopic response for placebo,upadacitinib 15 mg QD, and upadacitinib 30 mg QD innon-biologic-inadequate responders (Non-Bio-IR) and biologic-inadequateresponders (Bio-IR) is provided in FIG. 57C.

Clinical remission rates per PROs and per CDAI at each visit, as well ascorresponding 95% confidence intervals (CIs), are presented in FIG. 58and FIG. 59, respectively.

The proportion of subjects achieving steroid-free clinical remission perPRO among subjects on steroids at baseline for placebo, upadacitinib 15mg, and upadacitinib 30 mg is provide in FIG. 60A. Referring to FIG.60A, steroid-free clinical remission was achieved at Week 52 amongsubjects on steroids at baseline. Steroid-free+PRO Remission was definesas discontinuation of steroid AND achievement of clinical remission perPRO (average daily SF≤2.8 AND Average daily AP score ≤1 and both notworse than BL).

The proportion of subjects achieving steroid-free clinical remission perCDAI among subjects on steroids at baseline for placebo, upadacitinib 15mg, and upadacitinib 30 mg is provide in FIG. 60B. Referring to FIG.60B, steroid-free clinical remission was achieved at Week 52 amongsubjects on steroids at baseline. Steroid-free+CDAI Remission wasdefined as iscontinuation of steroid AND achievement of clinicalremission per CDAI (CDAI<150).

The proportion of subjects achieving steroid-free clinical remission perPRO and CDAI among all subjects is provided in FIGS. 60C and 60D,respectively. Referring to FIGS. 60c and 60D, steroid-free clinicalremission was achieved at Week 52 among all subjects per both PRO andCDAI.

The proportion of subjects achieving endoscopic response at Week 52 withfor placebo, upadacitinib 15 mg, and upadacitinib 30 mg is provided inFIG. 61A. Endoscopic response was defined as a decrease in SES-CD>50%from baseline (or for subjects with isolated ileal disease and abaseline SES-CD of 4, at least a 2-point reduction from baseline),scored by central reader.

The proportion of subjects achieving endoscopic remission at Week 52with for placebo, upadacitinib 15 mg, and upadacitinib 30 mg is providedin FIG. 61B. Endoscopic remission was defined as SES-CD≤4 and at least a2-point reduction versus baseline and no subscore greater than 1 in anyindividual variable, as scored by central reader.

The proportion of subjects achieving maintenance of clinical remissionper PROs and CDAI for placebo, upadacitinib 15 mg, and upadacitinib 30mg is provided in FIG. 62A, defined as clinical remission (per PROs orCDAI) at Week 52 among subjects in Clinical Remission at Week 0.

The proportion of subjects achieving deep remission per PROs and CDAIfor placebo, upadacitinib 15 mg, and upadacitinib 30 mg is provided inFIG. 62B, defined as achievement of clinical remission per PROs or CDAIand Endoscopic Remission at Week 52.

1-166. (canceled)
 167. A method of treating Crohn's disease in an adultpatient having moderately to severely active Crohn's disease, the methodcomprising: a. orally administering to the patient an induction dose of45 mg of upadacitinib once daily for 12 weeks; and b. orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 15 mg of upadacitinib once daily.168. The method of claim 167, wherein the patient achieves clinicalremission per Crohn's Disease Activity Index (CDAI) at 12 weeks afterthe administration of the initial induction dose of 45 mg ofupadacitinib.
 169. The method of claim 168, wherein the patient achievesclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 15 mg ofupadacitinib.
 170. The method of claim 167, wherein the adult patienthad an inadequate response or intolerance to a previous treatment withan anti-TNF agent.
 171. A method of treating Crohn's disease in an adultpatient having refractory or severely active Crohn's disease, the methodcomprising: a. orally administering to the patient an induction dose of45 mg of upadacitinib once daily for 12 weeks; and b. orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily.172. The method of claim 171, wherein the patient achieves clinicalremission per Crohn's Disease Activity Index (CDAI) at 12 weeks afterthe administration of the initial induction dose of 45 mg ofupadacitinib.
 173. The method of claim 171, wherein the patient achievesclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 30 mg ofupadacitinib.
 174. The method of claim 171, wherein the adult patienthad an inadequate response or intolerance to a previous treatment withan anti-TNF agent.
 175. A method of treating an adult patient sufferingfrom moderately to severely active Crohn's disease that is statisticallysignificantly superior to placebo, comprising orally administering oncedaily to the patient an induction dose of 45 mg of upadacitinib oncedaily for 12 weeks, wherein when the method is used to treat apopulation of human patients suffering from moderately to severelyactive Crohn's disease, a statistically significantly greater percentageof patients achieve clinical remission per Crohn's Disease ActivityIndex (CDAI) at 12 weeks after the administration of the initialinduction dose of 45 mg of upadacitinib compared to a control group ofhuman patients treated with placebo.
 176. The method of claim 175,wherein the adult patient had an inadequate response or intolerance to aprevious treatment with an anti-TNF agent.
 177. The method of claim 175,wherein the statistically significantly greater percentage of patientsachieving clinical remission per Crohn's Disease Activity Index (CDAI)has a p value of less than 0.001.
 178. The method of claim 175, furthercomprising orally administering to the patient, after the last inductiondose of 45 mg of upadacitinib, a maintenance dose of 15 mg ofupadacitinib once daily, wherein a statistically significantly greaterpercentage of patients achieve clinical remission per Crohn's DiseaseActivity Index (CDAI) at 52 weeks after the administration of theinitial maintenance dose of 15 mg of upadacitinib compared to a controlgroup of human patients treated with placebo.
 179. The method of claim178, wherein the adult patient had an inadequate response or intoleranceto a previous treatment with an anti-TNF agent.
 180. The method of claim178, wherein the statistically significantly greater percentage ofpatients achieving clinical remission per Crohn's Disease Activity Index(CDAI) has a p value of less than 0.001.
 181. The method of claim 175,wherein the adult patient is suffering from refractory or severelyactive Crohn's disease and the method further comprises orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 30 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 30mg of upadacitinib compared to a control group of human patients treatedwith placebo.
 182. The method of claim 181, wherein the adult patienthad an inadequate response or intolerance to a previous treatment withan anti-TNF agent.
 183. The method of claim 181, wherein thestatistically significantly greater percentage of patients achievingclinical remission per Crohn's Disease Activity Index (CDAI) has a pvalue of less than 0.001.
 184. A method of treating adult patientssuffering from moderately to severely active Crohn's disease that isstatistically significantly superior to placebo, comprising orallyadministering once daily to each patient an induction dose of 45 mg ofupadacitinib once daily for 12 weeks, wherein the method results in astatistically significantly greater percentage of patients achievingclinical remission per Crohn's Disease Activity Index (CDAI) at 12 weeksafter the administration of the initial induction dose of 45 mg ofupadacitinib compared to a control group of human patients treated withplacebo.
 185. The method of claim 184, wherein the adult patients havean inadequate response or intolerance to a previous treatment with ananti-TNF agent.
 186. The method of claim 184, wherein the statisticallysignificantly greater percentage of patients achieving clinicalremission per Crohn's Disease Activity Index (CDAI) has a p value ofless than 0.001.
 187. The method of claim 184, further comprising orallyadministering to the patient, after the last induction dose of 45 mg ofupadacitinib, a maintenance dose of 15 mg of upadacitinib once daily,wherein a statistically significantly greater percentage of patientsachieve clinical remission per Crohn's Disease Activity Index (CDAI) at52 weeks after the administration of the initial maintenance dose of 15mg of upadacitinib compared to a control group of human patients treatedwith placebo.
 188. The method of claim 187, wherein the adult patientshave an inadequate response or intolerance to a previous treatment withan anti-TNF agent.
 189. The method of claim 187, wherein thestatistically significantly greater percentage of patients achievingclinical remission per Crohn's Disease Activity Index (CDAI) has a pvalue of less than 0.001.
 190. The method of claim 184, wherein theadult patient is suffering from refractory or severely active Crohn'sdisease and the method further comprises orally administering to thepatient, after the last induction dose of 45 mg of upadacitinib, amaintenance dose of 30 mg of upadacitinib once daily, wherein astatistically significantly greater percentage of patients achieveclinical remission per Crohn's Disease Activity Index (CDAI) at 52 weeksafter the administration of the initial maintenance dose of 30 mg ofupadacitinib of upadacitinib compared to a control group of humanpatients treated with placebo.
 191. The method of claim 190, wherein theadult patients have an inadequate response or intolerance to a previoustreatment with an anti-TNF agent.
 192. The method of claim 190, whereinthe statistically significantly greater percentage of patients achievingclinical remission per Crohn's Disease Activity Index (CDAI) has a pvalue of less than 0.001.